Research in Parkinson's disease (PD) genetics has been extremely prolific over the past decade. More than 13 loci and 9 genes have been identified, but their implication in PD is not always certain. Point mutations, duplications and triplications in the α-synuclein (SNCA) gene cause a rare dominant form of PD in familial and sporadic cases. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a more frequent cause of autosomal dominant PD, particularly in certain ethnic groups. Loss-of-function mutations in Parkin, PINK1, DJ-1 and ATP13A2 cause autosomal recessive parkinsonism with early-onset. Identification of other Mendelian forms of PD will be a main challenge for the next decade. In addition, susceptibility variants that contribute to PD have been identified in several populations, such as polymorphisms in the SNCA, LRRK2 genes and heterozygous mutations in the β-glucocerebrosidase (GBA) gene. Genome-wide associations and re-sequencing projects, together with gene-environment interaction studies, are expected to further define the causal role of genetic determinants in the pathogenesis of PD, and improve prevention and treatment.

INTRODUCTION

Parkinson's disease (PD), the second most frequent neurodegenerative disorder after Alzheimer's disease (six million patients world-wide), is generally diagnosed after the sixth decade. It causes motor dysfunctions, such as bradykinesia, resting tremor, rigidity and postural instability, but also affects autonomic functions and cognition (1).

PD results mainly from progressive degeneration of dopaminergic neurons in the substantia nigra and other monoaminergic cell groups in the brainstem (2), increased microglial activation and accumulation of proteins in surviving dopaminergic neurons, known as Lewy bodies and Lewy neurites (3). Symptoms appear when 50–70% of nigrostriatal dopaminergic neurons have been lost. Thus, the population of undiagnosed asymptomatic patients is probably large. No treatment can slow progression of PD; levodopa and dopamine agonists only relieve symptoms (4).

The etiology of PD is unknown, although older age and neurotoxins are established risk factors, and smoking appears to be protective. In the last decade, several causative genes and susceptibility factors have been identified in rare families with Mendelian inheritance, and suggest that abnormal handling of misfolded proteins by the ubiquitin-proteasome and autophagy-lysosomal systems, increased oxidative stress, mitochondrial and lysosomal dysfunctions, and other pathogenic dysfunctions, contribute to PD. We review here the genetic findings of the last 18 months.

MONOGENIC FORMS OF PARKINSON'S DISEASE

Although PD was long considered a non-genetic disorder of ‘sporadic’ origin, 5–10% of patients are now known to have monogenic forms of the disease. At least, 13 loci and 9 genes (Table 1) are associated with both autosomal dominant (PARK1 and PARK4/α-Synuclein; PARK5/UCHL1; PARK8/LRRK2; PARK11/GIGYF2; PARK13/Omi/Htra2) and autosomal recessive (PARK2/Parkin; PARK6/PINK1; PARK7/DJ-1; PARK9/ATP13A2) PD.

Table 1.

Loci, genes and susceptibility factors involved in parkinsonism

PARK loci Gene Map position Forms of PD Mutations Susceptibility variants 
PD-associated loci and genes with conclusive evidence 
PARK1/PARK4 SNCA 4q21 EOPD AD and sporadic A30P, E46K, A53T, Genomic duplications/triplications Promotor Rep1, 5′ and 3′ variants ↑ risk for PD 
PARK8 LRRK2 12q12 LOPD AD and sporadic >40 missense variants, >7 of them pathogenic, including the common G2019S G2385R, R1628P ↑ risk for PD in Asian populations 
PARK2 Parkin 6q25–q27 Juvenile and EOPD AR and sporadic >100 mutations (point mutations, exonic rearrangements) Promoter polymorphisms ↑ risk for PD; heterozygous mutations may ↑ risk for LOPD 
PARK6 PINK1 1p35–p36 ARPD >40 point mutations, rare large deletions Heterozygous mutations may ↑ risk for LOPD 
PARK7 DJ-1 1p36 EOPD AR >10 point mutations and large deletions Heterozygous mutations may ↑ risk for LOPD 
PARK9 ATP13A2 1p36 Juvenile AR Kufor–Rakeb syndrome and EOPD >5 point mutations Heterozygous variants ↑ risk for PD 
PD-associated loci and genes with unknown relevance 
PARK3 Unknown 2p13 LOPD AD Not identified SPR variants may ↑ risk for PD 
PARK5 UCHL1 4p14 LOPD AD One mutation in a single PD sibling pair S18Y variant ↓ risk for PD 
PARK10 Unknown 1p32 Unclear Not identified ELAVL4, UPS24, RFN11 variants may ↑ risk for PD 
PARK11? GIGYF2 2q36–q37 LOPD AD Seven missense variants None 
PARK13 Omi/HTRA2 2p13 Unclear Two missense variants Regulatory variants may contribute to risk for PD 
PARK14? PLA2G6 22q13.1 Juvenile AR levodopa-responsive dystonia-parkinsonism Two missense mutations Not investigated 
PARK15? FBXO7 22q12–q13 EO AR parkinsonian-pyramidal syndrome Three point mutations Not investigated 
PARK12 Unknown Xq Unclear Not identified Unknown 
PD-associated genes proposed by candidate gene approach 
Not assigned SCA2 12q24.1 Unclear, dominant for SCA2 Low-range interrupted CAG expansions in SCA2 Not investigated 
Not assigned GBA 1q21 Unclear, recessive for GD  Heterozygous GD-associated mutations ↑ risk for PD 
PARK loci Gene Map position Forms of PD Mutations Susceptibility variants 
PD-associated loci and genes with conclusive evidence 
PARK1/PARK4 SNCA 4q21 EOPD AD and sporadic A30P, E46K, A53T, Genomic duplications/triplications Promotor Rep1, 5′ and 3′ variants ↑ risk for PD 
PARK8 LRRK2 12q12 LOPD AD and sporadic >40 missense variants, >7 of them pathogenic, including the common G2019S G2385R, R1628P ↑ risk for PD in Asian populations 
PARK2 Parkin 6q25–q27 Juvenile and EOPD AR and sporadic >100 mutations (point mutations, exonic rearrangements) Promoter polymorphisms ↑ risk for PD; heterozygous mutations may ↑ risk for LOPD 
PARK6 PINK1 1p35–p36 ARPD >40 point mutations, rare large deletions Heterozygous mutations may ↑ risk for LOPD 
PARK7 DJ-1 1p36 EOPD AR >10 point mutations and large deletions Heterozygous mutations may ↑ risk for LOPD 
PARK9 ATP13A2 1p36 Juvenile AR Kufor–Rakeb syndrome and EOPD >5 point mutations Heterozygous variants ↑ risk for PD 
PD-associated loci and genes with unknown relevance 
PARK3 Unknown 2p13 LOPD AD Not identified SPR variants may ↑ risk for PD 
PARK5 UCHL1 4p14 LOPD AD One mutation in a single PD sibling pair S18Y variant ↓ risk for PD 
PARK10 Unknown 1p32 Unclear Not identified ELAVL4, UPS24, RFN11 variants may ↑ risk for PD 
PARK11? GIGYF2 2q36–q37 LOPD AD Seven missense variants None 
PARK13 Omi/HTRA2 2p13 Unclear Two missense variants Regulatory variants may contribute to risk for PD 
PARK14? PLA2G6 22q13.1 Juvenile AR levodopa-responsive dystonia-parkinsonism Two missense mutations Not investigated 
PARK15? FBXO7 22q12–q13 EO AR parkinsonian-pyramidal syndrome Three point mutations Not investigated 
PARK12 Unknown Xq Unclear Not identified Unknown 
PD-associated genes proposed by candidate gene approach 
Not assigned SCA2 12q24.1 Unclear, dominant for SCA2 Low-range interrupted CAG expansions in SCA2 Not investigated 
Not assigned GBA 1q21 Unclear, recessive for GD  Heterozygous GD-associated mutations ↑ risk for PD 

EO, early-onset; LO, late-onset, AD, autosomal dominant; AR, autosomal recessive; PD, Parkinson's disease; GD, Gaucher's disease; SCA2, spinocerebellar ataxia type 2; SNCA, α-Synuclein; PINK1, PTEN-induced kinase 1; LRRK2, Leucine-Rich Repeat Kinase 2; SPR, sepiapterin reductase; UCHL1, ubiquitin carboxy-terminal hydrolase L1; ELAVL4, embryonic lethal, abnormal vision-like 4; GIGYF2, GRB10-interacting GYF protein 2; PLA2G6, group VI phospholipase A2; GBA, β glucocerebrosidase.

PARK1- and PARK4-linked PD: α-Synuclein (SNCA)

SNCA, unequivocally associated with familial parkinsonism (5), is central to the pathophysiology of familial and sporadic PD. The protein is the major component of Lewy bodies and Lewy neurites, in PD and other α-synucleinopathies (6,7).

Three missense mutations (A53T, A30P and E46K) (5,8,9) in SNCA (PARK1) are extremely rare (10). A53T, the most frequent, was found in at least 12 Mediterranean families, notably Greek and Italian, probably with a common ancestor (11). The A53T mutation also occurred on a different haplotye in a Korean family, suggesting two independent mutational events (12). Most patients with point mutations have prominent dementia, as in dementia with Lewy bodies (DLB), and earlier onset than in sporadic PD (13).

Duplications and triplications of the locus containing SNCA [initially PARK4 (14)] suggest that over-expression of SNCA is toxic. Nine families with duplications and three with triplications of the SNCA locus (1423) give an overall mutation frequency of ∼2% in familial parkinsonism (Table 2). In the recently reported Swedish-American family (19), genetic and genealogic studies revealed the coexistence of both SNCA duplication (Swedish branch) and triplication (American branch) within the same family. Although the rearrangements vary from 0.4 to 6.37 Mb, encompassing 1 to 33 genes, which suggests that they occurred independently, the severity of the phenotype appears to reflect SNCA dosage (four copies in triplications or homozygous duplications and three copies in heterozygous duplications), not the number of genes replicated (2123). Except for a few cases with dementia (1821,24,25), early stage patients with duplications resemble those with ‘idiopathic’ PD; those with triplications have earlier onset, faster disease progression, marked dementia and frequent dysautonomia (22). SNCA multiplications have age-dependent or incomplete penetrance, since they were also found in asymptomatic carriers who were older than the onset age of the probands and had normal SPECT neuroimaging (20). Apparently sporadic cases may therefore have SNCA duplications (20,26); one had a de novo rearrangement (27) (Table 2).

Table 2.

Overview of studies showing SNCA multiplications

Populations screened Origin No. of families or cases No. of mutation carrier families or cases Reference 
Familial forms with PD 
Iowa  (14
USA 42 1a (2.4%) (15,19
Japan 113 2 (1.8%) (18
Korea 37 1 (2.7%) (20
Europe, North Africa 294 5 (1.7%) (16,17,23
Japan  (21
Isolated cases with PD 
Japan 200 (18
Korea 869 2 (0.23%) (20
Europe, North Africa 101 1 (1.0%) (26
Germany 403 1 de novo (0.25%) (27
Populations screened Origin No. of families or cases No. of mutation carrier families or cases Reference 
Familial forms with PD 
Iowa  (14
USA 42 1a (2.4%) (15,19
Japan 113 2 (1.8%) (18
Korea 37 1 (2.7%) (20
Europe, North Africa 294 5 (1.7%) (16,17,23
Japan  (21
Isolated cases with PD 
Japan 200 (18
Korea 869 2 (0.23%) (20
Europe, North Africa 101 1 (1.0%) (26
Germany 403 1 de novo (0.25%) (27

aSwedish-American family with both SNCA duplication and triplication.

PARK8-linked PD: leucine-rich repeat kinase 2 (LRRK2)

LRRK2 mutations at the PARK8 locus are found in autosomal dominant parkinsonism (28,29), but also in much more frequent sporadic cases. This large 144 kb-gene, with 51 exons, encoding a 2527 amino-acid multi-domain protein accounts for up to 10% of autosomal dominant familial (3036, personal communication) and 3.6% of sporadic PD (37). More than 40 different variants, almost all missense, have been found (Fig. 1). The pathogenicity of many of these variants is unclear, however, because of reduced penetrance, phenocopies or the absence of segregation analyses due to late-onset and unknown parental genotypes. Seven seem to be proven pathogenic mutations, and are clustered in functionally important regions which are highly conserved through evolution (38,39).

Figure 1.

Schematic representation of LRRK2, its functional domains and its sequence changes. Lrrk2 has 2527 amino-acids and contains several conserved domains: ARM (Armadillo), ANK (Ankyrin repeat), LRR (leucine rich repeat), Roc (Ras of complex proteins: GTPase), COR (C-terminal of Roc), MAPKKK (mitogen activated kinase kinase kinase) and WD-40. Numbers under the protein line indicate the boundaries of each domain. Numbers above the gene line indicate the number of the exons carrying LRRK2 variants. Recurrent proven pathogenic mutations are in red and in bold. Potentially pathogenic mutations, for which cosegregation analyses were reported, are highlighted in bold. Variants of unknown significance, found in single PD patients, are highlighted in blue and in italics. Risk factors are shown in blue and in hatched box.

Figure 1.

Schematic representation of LRRK2, its functional domains and its sequence changes. Lrrk2 has 2527 amino-acids and contains several conserved domains: ARM (Armadillo), ANK (Ankyrin repeat), LRR (leucine rich repeat), Roc (Ras of complex proteins: GTPase), COR (C-terminal of Roc), MAPKKK (mitogen activated kinase kinase kinase) and WD-40. Numbers under the protein line indicate the boundaries of each domain. Numbers above the gene line indicate the number of the exons carrying LRRK2 variants. Recurrent proven pathogenic mutations are in red and in bold. Potentially pathogenic mutations, for which cosegregation analyses were reported, are highlighted in bold. Variants of unknown significance, found in single PD patients, are highlighted in blue and in italics. Risk factors are shown in blue and in hatched box.

The G2019S mutation, frequent in both familial (2–5%) and apparently sporadic (1–2%) European PD patients (3942), facilitates genetic testing, although it is also present in early-onset PD (<50 years) (38,43) and in a few healthy controls (4451). It may also be involved in other neurodegenerative disorders (52). The prevalence of G2019S is affected by ethnicity. Very rare in Asia (5356), South Africa (57), some European countries, such as Poland, Greece and Germany (36,5862), it accounts for 30–40% of familial and sporadic PD patients from North Africa and 10–30% of Ashkenazi Jews (49,50,6366).

Only three different haplotypes are found in G2019S carriers (6771). A common 193 kb genomic region, so-called haplotype 1 (69), is shared by 95% of G2019S carriers of European, North and South African and Ashkenazi Jewish origin (personal communication). The mutation probably arose in Ashkenazi Jews much earlier than in North African Arabs and Europeans, probably several thousand years ago in the Near-East (personal communication). The second rare haplotype is found in a total of five families of European ancestry (69, personal communication). The third, primarily in Japanese carriers (70), is also found in a Turkish family (personal communication).

The issue of penetrance of the common LRRK2 mutations is of clinical interest with implications for genetic counselling. The penetrance of G2019S-associated disease increased from 17% at age 50 to 85% at age 70 in an initial family-based study (68), but varied in subsequent reports, depending on sample size, study design (case–control or family-based methods), inclusion of probands in the analysis, methods of calculation (44,48,49,72). The international LRRK2 Consortium including 21 centers from North America and Europe determined the age-specific penetrance of the LRRK2 G2019S mutation to be 28% at 59, 51% at 69 and 74% at 79 years with no effect of the sex (39). However, ethnic group may influence penetrance, which was estimated at 45% in an Arab Berber case–control study (65), higher than in Ashkenazi Jews or in Italians [lifetime 35% (49,72)], but much lower than in the initial family-based studies [85–100% at age 80 (44,68)]. Ascertainment bias may explain the differences; when families with multiple affected members are over-represented, penetrance may be over-estimated. When corrected for by appropriate statistical analysis (73), penetrance was 67%, twice that in randomly ascertained sporadic PD patients. Additional genetic or environmental modifiers must affect penetrance in these families.

Comparison of G2019S carriers from the international LRRK2 Consortium with pathologically proven PD patients from the Queen Square Brain Bank showed their phenotype to be that of idiopathic PD, although some motor (disease severity, rate of progression, occurrence of falls and dyskinesia) and non-motor (cognition and olfaction) symptoms suggest that the disease is more benign in LRRK2 G2019S carriers than in patients with idiopathic PD (39). Unlike SNCA multiplications, dosage of mutant LRRK2 does not affect phenotype. Homozygous LRRK2 affected carriers or patients with LRRK2 and additional mutations in PD-associated genes such as Parkin, are similar to heterozygous LRRK2 carriers (50,64,66,74,75). In addition, a healthy control and three unaffected relatives with homozygous G2019S mutations were identified, one of whom was more than 70 years old (66,75), suggesting that the penetrance is reduced even when the two copies of LRRK2 are mutated.

PARK9-linked PD: ATP13A2

ATP13A2 is the causative gene at the PARK9 locus, mapped in a Jordanian and a Chilean family with Kufor–Rakeb syndrome (KRS), a recessive, juvenile onset atypical parkinsonism with pyramidal degeneration and cognitive dysfunction (76,77), who had homozygous (552LfsX788) and compound heterozygous (c.1305 + 5G >A/1019GfsX1021) mutations causing retention and proteosomal degradation of truncated proteins in the endoplasmic reticulum instead of insertion in lysosomal membranes (78). A Japanese patient with KRS-like disease but later onset had a homozygous ATP13A2 F182L mutation (79). Interestingly, two recent studies extended ATP13A2 mutational analysis to more typical early-onset parkinsonism. A homozygous G504R mutation was found in a Brazilian sporadic patient with juvenile parkinsonism, impaired upward gaze and moderate brain atrophy; two heterozygous variations were also found (80). A novel heterozygous variant was observed in three Asian patients with idiopathic PD, and might be a risk factor; one of them with earlier onset and more severe disease also had a heterozygous PINK1 variant (81).

Although homozygous and compound heterozygous mutations in ‘recessive’ parkinsonism-linked genes, Parkin, PINK1, DJ-1 and ATP13A2, are unequivocally associated with heritable parkinsonism and early-onset, the pathogenicity of the heterozygous mutations is still controversial. Some studies suggest that they may be susceptibility factors for later onset parkinsonism (82).

ATP13A2 encodes a large lysosomal P-type ATPase with 1180 amino-acids and 10 transmembrane domains. Since the lysosomal degradation pathway can clear SNCA aggregates by macroautophagy, lysosomal dysfunction, caused by mutations in ATP13A2 or β-glucocerebrosidase (GBA), that cause the lysosomal storage disorder Gaucher's disease (GD), might contribute to the pathogenesis of parkinsonism (83,84).

OTHER FORMS OF FAMILIAL PD

PARK11-linked PD: GRB10-interacting GYF protein 2 (GIGYF2)

Recently, it has been proposed that GIGYF2, also called TNRC15 (Trinucleotide Repeat Containing 15) corresponds to the PARK11 locus, previously identified by a whole genome linkage analysis in a population of familial PD (8587), since it contains the PARK11 microsatellite marker D2S206 with the highest Lodscore. In two independent French and Italian familial PD populations, 10 changes in 16 unrelated PD patients were found in the shortest form of GIGYF2, for a mutation frequency of 6.4% (88). GIGYF2 contains the GYF motif that binds to a proline-rich Grb10 adaptor protein (89), and potentially regulates cellular responses to insulin and insulin-like growth factor. No disease-causing mutations were found, however, in other European populations, mostly sporadic PD cases (90).

PARK13-linked PD: Omi/Htra2

Omi/Htra2, a mitochondrial-targeted serine protease released into the cytosol during apoptosis, has been implicated in PD pathogenesis on the basis of biological and genetic evidence (91). Omi/Htra2 knock-out and mutant mice present a neurodegenerative parkinsonian phenotype (92,93). Subsequently, a G399S mutation and an A141S risk factor were identified in a German case–control study (91), but no associations between PD and A141S or G399S were found in other studies (94,95). A novel R404W mutation and specific variants in the 5′ and 3′ regulatory regions of the Omi/Htra2 gene were found, however, in Belgian PD patients (96), extending the mutational spectrum to variants possibly affecting transcriptional activity. Genetic proof that Omi/Htra2 causes monogenic PD is lacking. In vitro, Omi/Htra2 is phosphorylated by PINK1 at a residue adjacent to G399S, increasing its proteolytic activity (97). Accordingly, Omi/Htra2 phosphorylation is decreased in brains of patients with PINK1 mutations (97). In Drosophilia, Omi/Htra2 acts downstream of PINK1, whereas Rhomboid-7, a mitochondrial protease, that interacts with PINK1, Parkin and Omi/Htra2 acts upstream of PINK1 (98).

Other PARK-linked PD or PD-causing genes

Other Mendelian forms of PD remain to be identified. The causal genes at several loci have not yet been identified (PARK12, chromosome Xq) (86), or the role of the candidate genes at these loci is still controversial (PARK3 and PARK10) (99,100). Two novel genes have been identified, however, in families with atypical PD.

An Iranian pedigree with a rare autosomal recessive parkinsonian-pyramidal syndrome (PPS) linked to chromosome 22 (101) had a homozygous R378G variation in FBXO7, a member of the F-box family of proteins active in the ubiquitin-proteasome protein degradation pathway (101,102). A homozygous truncating mutation (R498X) and compound heterozygous mutations (T22M/IVS7 + 1G >T) were identified in Italian and Dutch families with autosomal early-onset PPS (103).

In two unrelated Pakistani families with recessive adult-onset levodopa-responsive dystonia-parkinsonism, homozygous missense mutations were found in a phospholipase A2 gene (PLA2G6) on chromosome 22, encoding a calcium-independent group VI phospholipase A2 (104). Mutations in PLA2G6 cause two childhood neurologic disorders: infantile neuroaxonal dystrophy (INAD) and idiopathic neurodegeneration with brain iron accumulation (NBIA) (105,106). Unlike ATP13A2, mutations in FBXOZ and PLA2G6 genes are not yet known to cause typical parkinsonism.

Anticipation in familial parkinsonism suggests that dynamic mutations might cause the disease (107). Unexpectedly, CAG trinucleotide repeat expansions in the spinocerebellar ataxia type 2 (SCA2) gene, which mainly cause autosomal dominant cerebellar ataxias, often associated with deep sensory loss, slow ocular saccades, peripheral neuropathy and dementia (108), also cause familial or, more rarely, sporadic levodopa-responsive parkinsonism (109115). The prevalence of SCA2 mutations in autosomal dominant familial parkinsonism ranges from 1.5 to 8%, with the highest frequency in Chinese populations. The expansions are smaller (33 to 39 CAG in White PD patients, 33 to 47 CAG in Chinese patients) than in ataxic patients (109,110,116118), and are interrupted by one or more CAA, like large normal alleles (112114) whereas most expanded alleles of ataxic forms consist of an uninterrupted stretch of CAG (108). The interrupted expansions are stable within families (114,116,119) and CAA interruption may have a moderating influence on the phenotype by preventing somatic instability and high-range expansion. Whereas uninterrupted repeat expansion forms single hairpins that can sequester RNA-binding proteins, interruptions might lead to a different effect that would account for the marked difference in phenotype.

GENETIC SUSCEPTIBILITY FACTORS IN PARKINSON'S DISEASE

Monogenic forms represent less than 10% of PD in most populations. The vast majority result from complex interactions among genes and between genes and environmental factors. Genetic variations may be susceptibility factors or disease modifiers, affecting penetrance, age at onset, severity and progression. High-density arrays of single nucleotide polymorphisms (SNPs) permit the identification of susceptibility factors in genome-wide association (GWA) studies, in which the frequencies of putative risk alleles are compared in patients and controls.

Are genes responsible for monogenic disorders also susceptibility factors?

Associations detected by screening candidate genes in controls and patients cannot always be replicated in follow-up studies, and few candidate genes were confirmed in meta-analysis, because of potential biases and confounding factors, including population stratification, small sample size, misclassification and/or inappropriate statistical methods. Polymorphic variants in SNCA and LRRK2 genes, and heterozygous mutations in the GBA gene, however, have been validated as genetic susceptibility factors (Table 1).

Nucleotide polymorphisms located close to the promoter region and throughout SNCA have been associated with sporadic PD, although much of the data is equivocal (120128). Rep1 (D4S3481), a mixed nucleotide repeat, 10 kb upstream of the translational start of SNCA (129), has been confirmed as a risk factor (124), and synergy between an SNCA variant and a polymorphism in microtubule-associated protein tau (MAPT), each of which increases the risk for the development of PD, has been detected (130). The combination of risk genotypes in SNCA and MAPT doubles the risk of PD, further supporting the notion that the related pathways contribute to neurodegenerative diseases (131). The risk associated with Rep1 does not interact, however, with herbicide exposure, an independent risk factor in PD (132).

Two variants in the LRRK2 gene, G2385R and R1628P, confer susceptibility to PD in Asian populations. The former was associated with a 2- to 3-fold increase in risk in several independent Chinese populations from Singapore and Taiwan, and in Japanese and Koreans (133141). Our meta-analysis involving 3254 PD patients and 2515 controls from published studies showed an average carrier frequency of 9.6% in PD patients and 3.5% in controls with an overall odds ratio (OR) of 2.92 (95% CI 2.29–3.72, P < 0.0001). The variant is not found in Europeans (30,33), and is not a risk factor in Indians and Malays in Singapore (142). Age at onset, disease progression and levodopa-induced complications are similar in G2385R carriers and non-carriers (139,140,143), and no association was found with other neurodegenerative diseases or motor disorders (144146). The G2385 variant lies in the C-terminal WD40 domain of the LRRK2 protein thought to be involved in protein–protein interactions and might act through pro-apoptotic mechanism (136,147).

The R1628P variant, in the COR domain of the LRRK2 protein increases the risk of PD 2-fold (Table 3) (148150) in Chinese populations, but was not detected in Caucasian, Japanese and Indians (148,151), and was not associated with PD in Malays (151). R1628P-associated PD resembles idiopathic PD, even in homozygous patients. The phenotype is not more severe if G2385R and R1628P variants are combined (149).

Table 3.

Summary of association studies of the G2385R and R1628P variants as risk factors for PD

Study Population Patients with PD, n Carrier frequency in patients, n (%) Controls, n Carrier frequency in controls, n (%) P-value OR (95% CI) 
G2385R variant 
Di Fonzo et al. (133Chinese 608 61 (10) 373 18 (5) 0.0040 2.24 (1.29–3.88) 
Fung et al. (134Chinese 305 27 (9) 176 1 (0.5) 0.0002 16.99 (2.29–126.21) 
Farrer et al. (135Chinese 410 34 (8.3) 335 13 (3.9) 0.0140 2.24 (1.16–4.32) 
Tan et al. (136Chinese 494 37, including 1 HMZ (7.3) 495 18 (3.6) 0.0140 2.10 (1.10–3.90) 
Li et al. (137Chinese 235 14 (6) 214 0.0003 28.08 (1.66–473.72) 
Chan et al. (139Chinese 82 7, including 1 HMZ (8.5) 31 0.19 6.26 (0.35–112.92) 
An et al. (140Chinese 600 71, including 1 HMZ (11.8) 334 11 (3.3) 0.0001 3.94 (2.06–7.55) 
Funayama et al. (138Japanese 448 52 (11.6) 457 22 (4.8) 0.0001 2.60 (1.55–4.35) 
Choi et al. (141South Korean 72 9 (12.5) 100 5 (5) 0.0900 2.71 (0.87–8.28) 
Total  3254 312, including 3 HMZ (9.6) 2515 88 (3.5) 0.0001 2.92 (2.29–3.72) 
R1628P variant 
Ross et al. (148Chinese 1079 66, including 1 HMZ (6.5) 907 31 (3.4) 0.006 1.84 (1.20–2.83) 
Lu et al. (149Chinese 834 62, including 2 HMZ (6.5) 543 20 (3.7) 0.004 2.13 (1.29–3.52) 
Tan et al. (150Chinese 246 21 (8.4) 243 8 (3.4) 0.046 2.50 (1.10–5.60) 
Total  2159 149, including 3 HMZ (6.9) 1693 59 (3.5) 0.0001 2.05 (1.51–2.79) 
Study Population Patients with PD, n Carrier frequency in patients, n (%) Controls, n Carrier frequency in controls, n (%) P-value OR (95% CI) 
G2385R variant 
Di Fonzo et al. (133Chinese 608 61 (10) 373 18 (5) 0.0040 2.24 (1.29–3.88) 
Fung et al. (134Chinese 305 27 (9) 176 1 (0.5) 0.0002 16.99 (2.29–126.21) 
Farrer et al. (135Chinese 410 34 (8.3) 335 13 (3.9) 0.0140 2.24 (1.16–4.32) 
Tan et al. (136Chinese 494 37, including 1 HMZ (7.3) 495 18 (3.6) 0.0140 2.10 (1.10–3.90) 
Li et al. (137Chinese 235 14 (6) 214 0.0003 28.08 (1.66–473.72) 
Chan et al. (139Chinese 82 7, including 1 HMZ (8.5) 31 0.19 6.26 (0.35–112.92) 
An et al. (140Chinese 600 71, including 1 HMZ (11.8) 334 11 (3.3) 0.0001 3.94 (2.06–7.55) 
Funayama et al. (138Japanese 448 52 (11.6) 457 22 (4.8) 0.0001 2.60 (1.55–4.35) 
Choi et al. (141South Korean 72 9 (12.5) 100 5 (5) 0.0900 2.71 (0.87–8.28) 
Total  3254 312, including 3 HMZ (9.6) 2515 88 (3.5) 0.0001 2.92 (2.29–3.72) 
R1628P variant 
Ross et al. (148Chinese 1079 66, including 1 HMZ (6.5) 907 31 (3.4) 0.006 1.84 (1.20–2.83) 
Lu et al. (149Chinese 834 62, including 2 HMZ (6.5) 543 20 (3.7) 0.004 2.13 (1.29–3.52) 
Tan et al. (150Chinese 246 21 (8.4) 243 8 (3.4) 0.046 2.50 (1.10–5.60) 
Total  2159 149, including 3 HMZ (6.9) 1693 59 (3.5) 0.0001 2.05 (1.51–2.79) 

HMZ, homozygote; OR, odds ratio; CI, confidence interval.

Heterozygosity for a Mendelian disorder may confer risk to other complex diseases. Patients with GD, a recessively inherited deficiency of lysosomal GBA, may also have parkinsonism and Lewy bodies, and PD patients may have mutations in GBA (152166). The risk for PD associated with heterozygous and homozygous missense mutations in GBA was 7.0 (95% CI 4.2–11.4, P < 0.001) in Ashkenazi Jewish patients (152). In cases with four Jewish grand-parents, the GBA carrier frequency was 17 versus 8.0% in cases without known Jewish ancestry, and 22% in patients with onset ≤50 years versus 10% in patients with onset >50 years) (159). In a study focusing on mild and severe GBA mutations in PD patients, the GBA carrier frequency was 18% in patients versus 4% in elderly and 6% in young controls (163). Severe mutations increased the risk of PD by 13-fold, whereas mild mutations by only 2-fold. Fourteen percent of patients carried the frequent LRRK2 G2019S mutation, but only four patients carried both the LRRK2 G2019S mutation and a GBA mutation. Symptoms and onset in patients with digenic inheritance were unremarkable; the risks are therefore independent, not additive. GBA was also confirmed to be a susceptibility gene for familial PD in North America, associated with an earlier age at onset (164), and for dementia with Lewy bodies, a synucleopathy that shares pathological features with PD (167169). Mutations in GBA might cause lysosomal dysfunction or interfere with the binding of SNCA to its receptor at the lysosomal membrane, resulting in reduced SNCA degradation and cell toxicity (170,171).

The first genome-wide association studies in PD

GWA studies with high density arrays of several hundred thousand SNPs that capture a significant amount of the variation defined by the HapMap permit the identification of alleles with low penetrance undetectable by linkage studies. A two-stage GWA study with a 200K-SNP map (172) and a one-stage study with more informative markers (173) found no positive associations at the genome-wide significance level. There was little overlap in results between these two studies and the most strongly associated SNPs identified in the two-stage study were not replicated in several subsequent association studies (174). However, for the detection of genetic variants of small effect-sizes, these single studies are underpowered, which may be improved by combining genome-wide datasets with meta-analytic techniques which can also examine the between-dataset heterogeneity of GWAs (175). This strategy successfully identified new susceptibility alleles for PD in the GAK/DGKQ region on chromosome 4, in a recent GWA focusing on a large number of cases with positive history of PD, and confirmed the role of SNCA and MAPT in PD susceptibility (176). A combination of SNPs within axon guidance pathway genes that strongly predict PD susceptibility, age at onset and disease-free survival, was identified by genomic pathway approach and mining WGA datasets (177). The association between axon guidance genes and PD was not replicated, however (178).

CONCLUDING REMARKS AND FUTURE

Genes implicated in Mendelian forms of PD have provided new insights into the pathogenesis of the disease. The molecular pathways identified in monogenic cases may also be implicated in sporadic PD. The effect of dosage of SNCA on the phenotype of patients with duplications or triplications is illustrative. In addition, non-coding variants in this gene, thought to affect the level of expression in neurons, are associated with risk of the disease. The molecular mechanisms that contribute to PD and related disorders result in the death of dopaminergic neurons in vulnerable brain regions, and consequently the shared phenotype. However, known PD-causing genes account for only a small fraction of monogenic forms. Robust high-density SNP genotyping technologies and data analysis programs, combined with the analysis of copy number variations and large pathogenic genomic rearrangements, will identify novel loci. The clinical heterogeneity of parkinsonism is probably the cumulative effect of different gene-environment and/or gene–gene interactions. To identify risk variants in PD, association study methodology must be improved. Studies in isolated and heterogeneous populations, and approaches that minimize population stratification, are needed. Large-scale studies and publicly available GWA databases, crucial for statistical power, require collaborative efforts with shared sets of stringent clinical, genetic and analytic methods.

FUNDING

This work was supported by the Agence Nationale de la Recherche (ANR-05-NEUR-019).

ACKNOWLEDGEMENTS

We thank Merle Ruberg for critical reading of the manuscript.

Conflict of Interest statement. None declared.

REFERENCES

1
Poewe
W.
Non-motor symptoms in Parkinson's disease
Eur. J. Neurol.
 
2008
15
Suppl. 1
14
20
2
Braak
H.
Rub
U.
Gai
W.P.
Del Tredici
K.
Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen
J. Neural. Transm.
 
2003
110
517
536
3
Forno
L.S.
Neuropathology of Parkinson's disease
J. Neuropathol. Exp. Neurol.
 
1996
55
259
272
4
Schapira
A.H.
Present and future drug treatment for Parkinson's disease
J. Neurol. Neurosurg. Psychiatry
 
2005
76
1472
1478
5
Polymeropoulos
M.H.
Lavedan
C.
Leroy
E.
Ide
S.E.
Dehejia
A.
Dutra
A.
Pike
B.
Root
H.
Rubenstein
J.
Boyer
R.
et al.  
Mutation in the alpha-synuclein gene identified in families with Parkinson's disease
Science
 
1997
276
2045
2047
6
Spillantini
M.G.
Schmidt
M.L.
Lee
V.M.
Trojanowski
J.Q.
Jakes
R.
Goedert
M.
Alpha-synuclein in Lewy bodies
Nature
 
1997
388
839
840
7
Spillantini
M.G.
Crowther
R.A.
Jakes
R.
Hasegawa
M.
Goedert
M.
alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies
Proc. Natl Acad. Sci. USA
 
1998
95
6469
6473
8
Kruger
R.
Kuhn
W.
Muller
T.
Woitalla
D.
Graeber
M.
Kosel
S.
Przuntek
H.
Epplen
J.T.
Schols
L.
Riess
O.
Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease
Nat. Gen.
 
1998
18
106
108
9
Zarranz
J.J.
Alegre
J.
Gomez-Esteban
J.C.
Lezcano
E.
Ros
R.
Ampuero
I.
Vidal
L.
Hoenicka
J.
Rodriguez
O.
Atares
B.
et al.  
The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia
Ann. Neurol.
 
2004
55
164
173
10
Berg
D.
Niwar
M.
Maass
S.
Zimprich
A.
Moller
J.C.
Wuellner
U.
Schmitz-Hubsch
T.
Klein
C.
Tan
E.K.
Schols
L.
et al.  
Alpha-synuclein and Parkinson's disease: implications from the screening of more than 1,900 patients
Mov. Disord.
 
2005
20
1191
1194
11
Spira
P.J.
Sharpe
D.M.
Halliday
G.
Cavanagh
J.
Nicholson
G.A.
Clinical and pathological features of a Parkinsonian syndrome in a family with an Ala53Thr alpha-synuclein mutation
Ann. Neurol.
 
2001
49
313
319
12
Ki
C.S.
Stavrou
E.F.
Davanos
N.
Lee
W.Y.
Chung
E.J.
Kim
J.Y.
Athanassiadou
A.
The Ala53Thr mutation in the alpha-synuclein gene in a Korean family with Parkinson disease
Clin. Genet.
 
2007
71
471
473
13
Cookson
M.R.
Xiromerisiou
G.
Singleton
A.
How genetics research in Parkinson's disease is enhancing understanding of the common idiopathic forms of the disease
Curr. Opin. Neurol.
 
2005
18
706
711
14
Singleton
A.B.
Farrer
M.
Johnson
J.
Singleton
A.
Hague
S.
Kachergus
J.
Hulihan
M.
Peuralinna
T.
Dutra
A.
Nussbaum
R.
et al.  
alpha-Synuclein locus triplication causes Parkinson's disease
Science
 
2003
302
841
15
Farrer
M.
Kachergus
J.
Forno
L.
Lincoln
S.
Wang
D.S.
Hulihan
M.
Maraganore
D.
Gwinn-Hardy
K.
Wszolek
Z.
Dickson
D.
et al.  
Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications
Ann. Neurol.
 
2004
55
174
179
16
Chartier-Harlin
M.C.
Kachergus
J.
Roumier
C.
Mouroux
V.
Douay
X.
Lincoln
S.
Levecque
C.
Larvor
L.
Andrieux
J.
Hulihan
M.
et al.  
Alpha-synuclein locus duplication as a cause of familial Parkinson's disease
Lancet
 
2004
364
1167
1169
17
Ibanez
P.
Bonnet
A.M.
Debarges
B.
Lohmann
E.
Tison
F.
Pollak
P.
Agid
Y.
Durr
A.
Brice
A.
Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease
Lancet
 
2004
364
1169
1171
18
Nishioka
K.
Hayashi
S.
Farrer
M.J.
Singleton
A.B.
Yoshino
H.
Imai
H.
Kitami
T.
Sato
K.
Kuroda
R.
Tomiyama
H.
et al.  
Clinical heterogeneity of alpha-synuclein gene duplication in Parkinson's disease
Ann. Neurol.
 
2006
59
298
309
19
Fuchs
J.
Nilsson
C.
Kachergus
J.
Munz
M.
Larsson
E.M.
Schule
B.
Langston
J.W.
Middleton
F.A.
Ross
O.A.
Hulihan
M.
et al.  
Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication
Neurology
 
2007
68
916
922
20
Ahn
T.B.
Kim
S.Y.
Kim
J.Y.
Park
S.S.
Lee
D.S.
Min
H.J.
Kim
Y.K.
Kim
S.E.
Kim
J.M.
Kim
H.J.
et al.  
alpha-Synuclein gene duplication is present in sporadic Parkinson disease
Neurology
 
2008
70
43
49
21
Ikeuchi
T.
Kakita
A.
Shiga
A.
Kasuga
K.
Kaneko
H.
Tan
C.F.
Idezuka
J.
Wakabayashi
K.
Onodera
O.
Iwatsubo
T.
et al.  
Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia
Arch. Neurol.
 
2008
65
514
519
22
Ross
O.A.
Braithwaite
A.T.
Skipper
L.M.
Kachergus
J.
Hulihan
M.M.
Middleton
F.A.
Nishioka
K.
Fuchs
J.
Gasser
T.
Maraganore
D.M.
et al.  
Genomic investigation of alpha-synuclein multiplication and parkinsonism
Ann. Neurol.
 
2008
63
743
750
23
Ibanez
P.
Lesage
S.
Janin
S.
Lohman
E.
Durif
F.
Destee
A.
Bonnet
A.M.
Brefel-Courbon
C.
Heath
S.
Zelenika
D.
et al.  
α-Synuclein gene rearrangements in dominantly inherited parkinsonism. Frequency, phenotype, and mechanisms
Arch. Neurol.
 
2009
66
102
108
24
Obi
T.
Nishioka
K.
Ross
O.A.
Terada
T.
Yamazaki
K.
Sugiura
A.
Takanashi
M.
Mizoguchi
K.
Mori
H.
Mizuno
Y.
et al.  
Clinicopathologic study of a SNCA gene duplication patient with Parkinson disease and dementia
Neurology
 
2008
70
238
241
25
Uchiyama
T.
Ikeuchi
T.
Ouchi
Y.
Sakamoto
M.
Kasuga
K.
Shiga
A.
Suzuki
M.
Ito
M.
Atsumi
T.
Shimizu
T.
et al.  
Prominent psychiatric symptoms and glucose hypometabolism in a family with a SNCA duplication
Neurology
 
2008
71
1289
1291
26
Troiano
A.R.
Cazeneuve
C.
Le Ber
I.
Bonnet
A.M.
Lesage
S.
Brice
A.
Re: Alpha-synuclein gene duplication is present in sporadic Parkinson disease
Neurology
 
2008
71
1295
Author reply 1295
27
Brueggemann
N.
Odin
P.
Gruenewald
A.
Tadic
V.
Hagenah
J.
Seidel
G.
Lohmann
K.
Klein
C.
Djarmati
A.
Re: Alpha-synuclein gene duplication is present in sporadic Parkinson disease
Neurology
 
2008
71
1294
Author reply 1294
28
Paisan-Ruiz
C.
Jain
S.
Evans
E.W.
Gilks
W.P.
Simon
J.
van der Brug
M.
Lopez de Munain
A.
Aparicio
S.
Gil
A.M.
Khan
N.
et al.  
Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease
Neuron
 
2004
44
595
600
29
Zimprich
A.
Biskup
S.
Leitner
P.
Lichtner
P.
Farrer
M.
Lincoln
S.
Kachergus
J.
Hulihan
M.
Uitti
R.J.
Calne
D.B.
et al.  
Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology
Neuron
 
2004
44
601
607
30
Berg
D.
Schweitzer
K.
Leitner
P.
Zimprich
A.
Lichtner
P.
Belcredi
P.
Brussel
T.
Schulte
C.
Maass
S.
Nagele
T.
Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson's disease*
Brain
 
2005
128
3000
3011
31
Mata
I.F.
Kachergus
J.M.
Taylor
J.P.
Lincoln
S.
Aasly
J.
Lynch
T.
Hulihan
M.M.
Cobb
S.A.
Wu
R.M.
Lu
C.S.
et al.  
Lrrk2 pathogenic substitutions in Parkinson's disease
Neurogenetics
 
2005
6
171
177
32
Khan
N.L.
Jain
S.
Lynch
J.M.
Pavese
N.
Abou-Sleiman
P.
Holton
J.L.
Healy
D.G.
Gilks
W.P.
Sweeney
M.G.
Ganguly
M.
et al.  
Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data
Brain
 
2005
128
2786
2796
33
Di Fonzo
A.
Tassorelli
C.
De Mari
M.
Chien
H.F.
Ferreira
J.
Rohe
C.F.
Riboldazzi
G.
Antonini
A.
Albani
G.
Mauro
A.
et al.  
Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease
Eur. J. Hum. Genet.
 
2006
14
322
331
34
Johnson
J.
Paisan-Ruiz
C.
Lopez
G.
Crews
C.
Britton
A.
Malkani
R.
Evans
E.W.
McInerney-Leo
A.
Jain
S.
Nussbaum
R.L.
et al.  
Comprehensive screening of a North American Parkinson's disease cohort for LRRK2 mutation
Neurodegener. Dis.
 
2007
4
386
391
35
Nichols
W.C.
Elsaesser
V.E.
Pankratz
N.
Pauciulo
M.W.
Marek
D.K.
Halter
C.A.
Rudolph
A.
Shults
C.W.
Foroud
T.
LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8
Neurology
 
2007
69
1737
1744
36
Xiromerisiou
G.
Hadjigeorgiou
G.M.
Gourbali
V.
Johnson
J.
Papakonstantinou
I.
Papadimitriou
A.
Singleton
A.B.
Screening for SNCA and LRRK2 mutations in Greek sporadic and autosomal dominant Parkinson's disease: identification of two novel LRRK2 variants
Eur. J. Neurol.
 
2007
14
7
11
37
Paisan-Ruiz
C.
Nath
P.
Washecka
N.
Gibbs
J.R.
Singleton
A.B.
Comprehensive analysis of LRRK2 in publicly available Parkinson's disease cases and neurologically normal controls
Hum. Mutat.
 
2008
29
485
490
38
Hedrich
K.
Winkler
S.
Hagenah
J.
Kabakci
K.
Kasten
M.
Schwinger
E.
Volkmann
J.
Pramstaller
P.P.
Kostic
V.
Vieregge
P.
et al.  
Recurrent LRRK2 (Park8) mutations in early-onset Parkinson's disease
Mov. Disord.
 
2006
21
1506
1510
39
Healy
D.G.
Falchi
M.
O'sullivan
S.S.
Bonifati
V.
Durr
A.
Bressman
S.
Brice
A.
Aasly
J.
Zabetian
C.P.
Goldwurm
S.
et al.  
Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case–control study
Lancet Neurol.
 
2008
7
583
590
40
Di Fonzo
A.
Rohe
C.F.
Ferreira
J.
Chien
H.F.
Vacca
L.
Stocchi
F.
Guedes
L.
Fabrizio
E.
Manfredi
M.
Vanacore
N.
et al.  
A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease
Lancet
 
2005
365
412
415
41
Nichols
W.C.
Pankratz
N.
Hernandez
D.
Paisan-Ruiz
C.
Jain
S.
Halter
C.A.
Michaels
V.E.
Reed
T.
Rudolph
A.
Shults
C.W.
et al.  
Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease
Lancet
 
2005
365
410
412
42
Gilks
W.P.
Abou-Sleiman
P.M.
Gandhi
S.
Jain
S.
Singleton
A.
Lees
A.J.
Shaw
K.
Bhatia
K.P.
Bonifati
V.
Quinn
N.P.
et al.  
A common LRRK2 mutation in idiopathic Parkinson's disease
Lancet
 
2005
365
415
416
43
Mellick
G.D.
Siebert
G.A.
Funayama
M.
Buchanan
D.D.
Li
Y.
Imamichi
Y.
Yoshino
H.
Silburn
P.A.
Hattori
N.
Screening PARK genes for mutations in early-onset Parkinson's disease patients from Queensland, Australia
Parkinsonism Relat. Disord
 
2008
Epub ahead of print May 15, 2008
44
Lesage
S.
Ibanez
P.
Lohmann
E.
Pollak
P.
Tison
F.
Tazir
M.
Leutenegger
A.L.
Guimaraes
J.
Bonnet
A.M.
Agid
Y.
et al.  
G2019S LRRK2 mutation in French and North African families with Parkinson's disease
Ann. Neurol.
 
2005
58
784
787
45
Farrer
M.
Stone
J.
Mata
I.F.
Lincoln
S.
Kachergus
J.
Hulihan
M.
Strain
K.J.
Maraganore
D.M.
LRRK2 mutations in Parkinson disease
Neurology
 
2005
65
738
740
46
Kay
D.M.
Kramer
P.
Higgins
D.
Zabetian
C.P.
Payami
H.
Escaping Parkinson's disease: a neurologically healthy octogenarian with the LRRK2 G2019S mutation
Mov. Disord.
 
2005
20
1077
1078
47
Carmine Belin
A.
Westerlund
M.
Sydow
O.
Lundstromer
K.
Hakansson
A.
Nissbrandt
H.
Olson
L.
Galter
D.
Leucine-rich repeat kinase 2 (LRRK2) mutations in a Swedish Parkinson cohort and a healthy nonagenarian
Mov. Disord.
 
2006
21
1731
1734
48
Clark
L.N.
Wang
Y.
Karlins
E.
Saito
L.
Mejia-Santana
H.
Harris
J.
Louis
E.D.
Cote
L.J.
Andrews
H.
Fahn
S.
et al.  
Frequency of LRRK2 mutations in early- and late-onset Parkinson disease
Neurology
 
2006
67
1786
1791
49
Ozelius
L.J.
Senthil
G.
Saunders-Pullman
R.
Ohmann
E.
Deligtisch
A.
Tagliati
M.
Hunt
A.L.
Klein
C.
Henick
B.
Hailpern
S.M.
et al.  
LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews
N. Engl. J. Med.
 
2006
354
424
425
50
Lesage
S.
Durr
A.
Tazir
M.
Lohmann
E.
Leutenegger
A.L.
Janin
S.
Pollak
P.
Brice
A.
LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs
N. Engl. J. Med.
 
2006
354
422
423
51
Change
N.
Mercier
G.
Lucotte
G.
Genetic screening of the G2019S mutation of the LRRK2 gene in Southwest European, North African, and Sephardic Jewish subjects
Genet. Test.
 
2008
12
333
339
52
Chen-Plotkin
A.S.
Yuan
W.
Anderson
C.
McCarty Wood
E.
Hurtig
H.I.
Clark
C.M.
Miller
B.L.
Lee
V.M.
Trojanowski
J.Q.
Grossman
M.
et al.  
Corticobasal syndrome and primary progressive aphasia as manifestations of LRRK2 gene mutations
Neurology
 
2008
70
521
527
53
Tan
E.K.
Shen
H.
Tan
L.C.
Farrer
M.
Yew
K.
Chua
E.
Jamora
R.D.
Puvan
K.
Puong
K.Y.
Zhao
Y.
et al.  
The G2019S LRRK2 mutation is uncommon in an Asian cohort of Parkinson's disease patients
Neurosci. Lett.
 
2005
384
327
329
54
Lu
C.S.
Simons
E.J.
Wu-Chou
Y.H.
Fonzo
A.D.
Chang
H.C.
Chen
R.S.
Weng
Y.H.
Rohe
C.F.
Breedveld
G.J.
Hattori
N.
et al.  
The LRRK2 I2012T, G2019S, and I2020T mutations are rare in Taiwanese patients with sporadic Parkinson's disease
Parkinsonism Relat. Disord.
 
2005
11
521
522
55
Fung
H.C.
Chen
C.M.
Hardy
J.
Hernandez
D.
Singleton
A.
Wu
Y.R.
Lack of G2019S LRRK2 mutation in a cohort of Taiwanese with sporadic Parkinson's disease
Mov. Disord.
 
2006
21
880
881
56
Punia
S.
Behari
M.
Govindappa
S.T.
Swaminath
P.V.
Jayaram
S.
Goyal
V.
Muthane
U.B.
Juyal
R.C.
Thelma
B.K.
Absence/rarity of commonly reported LRRK2 mutations in Indian Parkinson's disease patients
Neurosci. Lett.
 
2006
409
83
88
57
Okubadejo
N.
Britton
A.
Crews
C.
Akinyemi
R.
Hardy
J.
Singleton
A.
Bras
J.
Analysis of Nigerians with apparently sporadic Parkinson disease for mutations in LRRK2, PRKN and ATXN3
PLoS ONE
 
2008
3
e3421
58
Bialecka
M.
Hui
S.
Klodowska-Duda
G.
Opala
G.
Tan
E.K.
Drozdzik
M.
Analysis of LRRK 2 G 2019 S and I 2020 T mutations in Parkinson's disease
Neurosci. Lett.
 
2005
390
1
3
59
Papapetropoulos
S.
Argyriou
A.A.
Mitsi
G.
Chroni
E.
Re: The G2019S LRRK2 mutation is uncommon amongst Greek patients with familial Parkinson's disease
Eur. J. Neurol.
 
2007
14
e6
60
Kalinderi
K.
Fidani
L.
Bostantjopoulou
S.
Katsarou
Z.
Kotsis
A.
The G2019S LRRK2 mutation is uncommon amongst Greek patients with sporadic Parkinson's disease
Eur. J. Neurol.
 
2007
14
1088
1090
61
Schlitter
A.M.
Woitalla
D.
Mueller
T.
Epplen
J.T.
Dekomien
G.
The LRRK2 gene in Parkinson's disease: mutation screening in patients from Germany
J. Neurol. Neurosurg. Psychiatry
 
2006
77
891
892
62
Moller
J.C.
Rissling
I.
Mylius
V.
Hoft
C.
Eggert
K.M.
Oertel
W.H.
The prevalence of the G2019S and R1441C/G/H mutations in LRRK2 in German patients with Parkinson's disease
Eur. J. Neurol.
 
2008
15
743
745
63
Orr-Urtreger
A.
Shifrin
C.
Rozovski
U.
Rosner
S.
Bercovich
D.
Gurevich
T.
Yagev-More
H.
Bar-Shira
A.
Giladi
N.
The LRRK2 G2019S mutation in Ashkenazi Jews with Parkinson disease: is there a gender effect?
Neurology
 
2007
69
1595
1602
64
Ishihara
L.
Gibson
R.A.
Warren
L.
Amouri
R.
Lyons
K.
Wielinski
C.
Hunter
C.
Swartz
J.E.
Elango
R.
Akkari
P.A.
et al.  
Screening for Lrrk2 G2019S and clinical comparison of Tunisian and North American Caucasian Parkinson's disease families
Mov. Disord.
 
2007
22
55
61
65
Hulihan
M.M.
Ishihara-Paul
L.
Kachergus
J.
Warren
L.
Amouri
R.
Elango
R.
Prinjha
R.K.
Upmanyu
R.
Kefi
M.
Zouari
M.
et al.  
LRRK2 Gly2019Ser penetrance in Arab-Berber patients from Tunisia: a case–control genetic study
Lancet Neurol.
 
2008
7
591
594
66
Lesage
S.
Belarbi
S.
Troiano
A.
Condroyer
C.
Hecham
N.
Pollak
P.
Lohman
E.
Benhassine
T.
Ysmail-Dahlouk
F.
Durr
A.
et al.  
Is the common LRRK2 G2019S mutation related to dyskinesias in North African Parkinson disease?
Neurology
 
2008
71
1550
1552
67
Lesage
S.
Leutenegger
A.L.
Ibanez
P.
Janin
S.
Lohmann
E.
Durr
A.
Brice
A.
LRRK2 haplotype analyses in European and North African families with Parkinson disease: a common founder for the G2019S mutation dating from the 13th century
Am. J. Hum. Genet.
 
2005
77
330
332
68
Kachergus
J.
Mata
I.F.
Hulihan
M.
Taylor
J.P.
Lincoln
S.
Aasly
J.
Gibson
J.M.
Ross
O.A.
Lynch
T.
Wiley
J.
et al.  
Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations
Am. J. Hum. Genet.
 
2005
76
672
680
69
Zabetian
C.P.
Hutter
C.M.
Yearout
D.
Lopez
A.N.
Factor
S.A.
Griffith
A.
Leis
B.C.
Bird
T.D.
Nutt
J.G.
Higgins
D.S.
et al.  
LRRK2 G2019S in families with Parkinson disease who originated from Europe and the Middle East: evidence of two distinct founding events beginning two millennia ago
Am. J. Hum. Genet.
 
2006
79
752
758
70
Zabetian
C.P.
Morino
H.
Ujike
H.
Yamamoto
M.
Oda
M.
Maruyama
H.
Izumi
Y.
Kaji
R.
Griffith
A.
Leis
B.C.
et al.  
Identification and haplotype analysis of LRRK2 G2019S in Japanese patients with Parkinson disease
Neurology
 
2006
67
697
699
71
Warren
L.
Gibson
R.
Ishihara
L.
Elango
R.
Xue
Z.
Akkari
A.
Ragone
L.
Pahwa
R.
Jankovic
J.
Nance
M.
et al.  
A founding LRRK2 haplotype shared by Tunisian, US, European and Middle Eastern families with Parkinson's disease
Parkinsonism Relat. Disord.
 
2008
14
77
80
72
Goldwurm
S.
Zini
M.
Mariani
L.
Tesei
S.
Miceli
R.
Sironi
F.
Clementi
M.
Bonifati
V.
Pezzoli
G.
Evaluation of LRRK2 G2019S penetrance: relevance for genetic counseling in Parkinson disease
Neurology
 
2007
68
1141
1143
73
Latourelle
J.C.
Sun
M.
Lew
M.F.
Suchowersky
O.
Klein
C.
Golbe
L.I.
Mark
M.H.
Growdon
J.H.
Wooten
G.F.
Watts
R.L.
et al.  
The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study
BMC Med.
 
2008
6
32
74
Dachsel
J.C.
Mata
I.F.
Ross
O.A.
Taylor
J.P.
Lincoln
S.J.
Hinkle
K.M.
Huerta
C.
Ribacoba
R.
Blazquez
M.
Alvarez
V.
et al.  
Digenic parkinsonism: investigation of the synergistic effects of PRKN and LRRK2
Neurosci. Lett.
 
2006
410
80
84
75
Ishihara
L.
Warren
L.
Gibson
R.
Amouri
R.
Lesage
S.
Durr
A.
Tazir
M.
Wszolek
Z.K.
Uitti
R.J.
Nichols
W.C.
et al.  
Clinical features of Parkinson disease patients with homozygous leucine-rich repeat kinase 2 G2019S mutations
Arch. Neurol.
 
2006
63
1250
1254
76
Najim al-Din
A.S.
Wriekat
A.
Mubaidin
A.
Dasouki
M.
Hiari
M.
Pallido-pyramidal degeneration, supranuclear upgaze paresis and dementia: Kufor-Rakeb syndrome
Acta Neurol. Scand.
 
1994
89
347
352
77
Hampshire
D.J.
Roberts
E.
Crow
Y.
Bond
J.
Mubaidin
A.
Wriekat
A.L.
Al-Din
A.
Woods
C.G.
Kufor-Rakeb syndrome, pallido-pyramidal degeneration with supranuclear upgaze paresis and dementia, maps to 1p36
J. Med. Gen.
 
2001
38
680
682
78
Ramirez
A.
Heimbach
A.
Grundemann
J.
Stiller
B.
Hampshire
D.
Cid
L.P.
Goebel
I.
Mubaidin
A.F.
Wriekat
A.L.
Roeper
J.
et al.  
Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase
Nat. Gen.
 
2006
38
1184
1191
79
Ning
Y.P.
Kanai
K.
Tomiyama
H.
Li
Y.
Funayama
M.
Yoshino
H.
Sato
S.
Asahina
M.
Kuwabara
S.
Takeda
A.
et al.  
PARK9-linked parkinsonism in eastern Asia: mutation detection in ATP13A2 and clinical phenotype
Neurology
 
2008
70
1491
1493
80
Di Fonzo
A.
Chien
H.F.
Socal
M.
Giraudo
S.
Tassorelli
C.
Iliceto
G.
Fabbrini
G.
Marconi
R.
Fincati
E.
Abbruzzese
G.
et al.  
ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease
Neurology
 
2007
68
1557
1562
81
Lin
C.H.
Tan
E.K.
Chen
M.L.
Tan
L.C.
Lim
H.Q.
Chen
G.S.
Wu
R.M.
Novel ATP13A2 variant associated with Parkinson disease in Taiwan and Singapore
Neurology
 
2008
71
1727
1732
82
Klein
C.
Lohmann-Hedrich
K.
Rogaeva
E.
Schlossmacher
M.G.
Lang
A.E.
Deciphering the role of heterozygous mutations in genes associated with parkinsonism
Lancet Neurol.
 
2007
6
652
662
83
Aharon-Peretz
J.
Badarny
S.
Rosenbaum
H.
Gershoni-Baruch
R.
Mutations in the glucocerebrosidase gene and Parkinson disease: phenotype–genotype correlation
Neurology
 
2005
65
1460
1461
84
Pan
T.
Kondo
S.
Le
W.
Jankovic
J.
The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson's disease
Brain
 
2008
131
1969
1978
85
Pankratz
N.
Nichols
W.C.
Uniacke
S.K.
Halter
C.
Rudolph
A.
Shults
C.
Conneally
P.M.
Foroud
T.
Genome screen to identify susceptibility genes for Parkinson disease in a sample without parkin mutations
Am. J. Hum. Genet.
 
2002
71
124
135
86
Pankratz
N.
Nichols
W.C.
Uniacke
S.K.
Halter
C.
Murrell
J.
Rudolph
A.
Shults
C.W.
Conneally
P.M.
Foroud
T.
Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families
Hum. Mol. Genet.
 
2003
12
2599
2608
87
Pankratz
N.
Nichols
W.C.
Uniacke
S.K.
Halter
C.
Rudolph
A.
Shults
C.
Conneally
P.M.
Foroud
T.
Significant linkage of Parkinson disease to chromosome 2q36–37
Am. J. Hum. Genet.
 
2003
72
1053
1057
88
Lautier
C.
Goldwurm
S.
Durr
A.
Giovannone
B.
Tsiaras
W.G.
Pezzoli
G.
Brice
A.
Smith
R.J.
Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease
Am. J. Hum. Genet.
 
2008
82
822
833
89
Giovannone
B.
Lee
E.
Laviola
L.
Giorgino
F.
Cleveland
K.A.
Smith
R.J.
Two novel proteins that are linked to insulin-like growth factor (IGF-I) receptors by the Grb10 adapter and modulate IGF-I signaling
J. Biol. Chem.
 
2003
278
31564
31573
90
Bras
J.
Simon-Sanchez
J.
Federoff
M.
Morgadinho
A.
Januario
C.
Ribeiro
M.
Cunha
L.
Oliveira
C.
Singleton
A.B.
Lack of replication of association between GIGYF2 variants and Parkinson disease
Hum. Mol. Gen.
 
2009
18
341
346
91
Strauss
K.M.
Martins
L.M.
Plun-Favreau
H.
Marx
F.P.
Kautzmann
S.
Berg
D.
Gasser
T.
Wszolek
Z.
Muller
T.
Bornemann
A.
et al.  
Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease
Hum. Mol. Genet.
 
2005
14
2099
2111
92
Jones
J.M.
Datta
P.
Srinivasula
S.M.
Ji
W.
Gupta
S.
Zhang
Z.
Davies
E.
Hajnoczky
G.
Saunders
T.L.
Van Keuren
M.L.
et al.  
Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice
Nature
 
2003
425
721
727
93
Martins
L.M.
Morrison
A.
Klupsch
K.
Fedele
V.
Moisoi
N.
Teismann
P.
Abuin
A.
Grau
E.
Geppert
M.
Livi
G.P.
et al.  
Neuroprotective role of the reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice
Mol. Cell. Biol.
 
2004
24
9848
9862
94
Simon-Sanchez
J.
Singleton
A.B.
Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic mutations in neurologically normal controls
Hum. Mol. Genet.
 
2008
17
1988
1993
95
Ross
O.A.
Soto
A.I.
Vilarino-Guell
C.
Heckman
M.G.
Diehl
N.N.
Hulihan
M.M.
Aasly
J.O.
Sando
S.
Gibson
J.M.
Lynch
T.
et al.  
Genetic variation of Omi/HtrA2 and Parkinson's disease
Parkinsonism Relat. Disord.
 
2008
14
539
543
96
Bogaerts
V.
Nuytemans
K.
Reumers
J.
Pals
P.
Engelborghs
S.
Pickut
B.
Corsmit
E.
Peeters
K.
Schymkowitz
J.
De Deyn
P.P.
et al.  
Genetic variability in the mitochondrial serine protease HTRA2 contributes to risk for Parkinson disease
Hum. Mutat.
 
2008
29
832
840
97
Plun-Favreau
H.
Klupsch
K.
Moisoi
N.
Gandhi
S.
Kjaer
S.
Frith
D.
Harvey
K.
Deas
E.
Harvey
R.J.
McDonald
N.
et al.  
The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1
Nat. Cell Biol.
 
2007
9
1243
1252
98
Whitworth
A.J.
Lee
J.R.
Ho
V.M.
Flick
R.
Chowdhury
R.
McQuibban
G.A.
Rhomboid-7 and HtrA2/Omi act in a common pathway with the Parkinson's disease factors Pink1 and Parkin
Dis. Models Mech.
 
2008
1
168
174
99
Gasser
T.
Muller-Myhsok
B.
Wszolek
Z.K.
Oehlmann
R.
Calne
D.B.
Bonifati
V.
Bereznai
B.
Fabrizio
E.
Vieregge
P.
Horstmann
R.D.
A susceptibility locus for Parkinson's disease maps to chromosome 2p13
Nat. Genet.
 
1998
18
262
265
100
Hicks
A.A.
Petursson
H.
Jonsson
T.
Stefansson
H.
Johannsdottir
H.S.
Sainz
J.
Frigge
M.L.
Kong
A.
Gulcher
J.R.
Stefansson
K.
et al.  
A susceptibility gene for late-onset idiopathic Parkinson's disease
Ann. Neurol.
 
2002
52
549
555
101
Shojaee
S.
Sina
F.
Banihosseini
S.S.
Kazemi
M.H.
Kalhor
R.
Shahidi
G.A.
Fakhrai-Rad
H.
Ronaghi
M.
Elahi
E.
Genome-wide linkage analysis of a Parkinsonian-pyramidal syndrome pedigree by 500 K SNP arrays
Am. J. Hum. Genet.
 
2008
82
1375
1384
102
Ho
M.S.
Ou
C.
Chan
Y.R.
Chien
C.T.
Pi
H.
The utility F-box for protein destruction
Cell Mol. Life Sci.
 
2008
65
1977
2000
103
Di Fonzo
A.
Dekker
M.C.
Montagna
P.
Baruzzi
A.
Yonova
E.H.
Correia Guedes
L.
Szczerbinska
A.
Zhao
T.
Dubbel-Hulsman
L.O.
Wouters
C.H.
et al.  
FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome
Neurology
 
2008
Epub ahead of print November 26, 2008
104
Paisan-Ruiz
C.
Bhatia
K.P.
Li
A.
Hernandez
D.
Davis
M.
Wood
N.W.
Hardy
J.
Houlden
H.
Singleton
A.
Schneider
S.A.
Characterization of PLA2G6 as a locus for dystonia-parkinsonism
Ann. Neurol
 
2008
Epub ahead of print June 20, 2008
105
Morgan
N.V.
Westaway
S.K.
Morton
J.E.
Gregory
A.
Gissen
P.
Sonek
S.
Cangul
H.
Coryell
J.
Canham
N.
Nardocci
N.
et al.  
PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron
Nat. Genet.
 
2006
38
752
754
106
Gregory
A.
Westaway
S.K.
Holm
I.E.
Kotzbauer
P.T.
Hogarth
P.
Sonek
S.
Coryell
J.C.
Nguyen
T.M.
Nardocci
N.
Zorzi
G.
et al.  
Neurodegeneration associated with genetic defects in phospholipase A(2)
Neurology
 
2008
71
1402
1409
107
Payami
H.
Bernard
S.
Larsen
K.
Kaye
J.
Nutt
J.
Genetic anticipation in Parkinson's disease
Neurology
 
1995
45
135
138
108
Cancel
G.
Durr
A.
Didierjean
O.
Imbert
G.
Burk
K.
Lezin
A.
Belal
S.
Benomar
A.
Abada-Bendib
M.
Vial
C.
et al.  
Molecular and clinical correlations in spinocerebellar ataxia 2: a study of 32 families
Hum. Mol. Genet.
 
1997
6
709
715
109
Payami
H.
Nutt
J.
Gancher
S.
Bird
T.
McNeal
M.G.
Seltzer
W.K.
Hussey
J.
Lockhart
P.
Gwinn-Hardy
K.
Singleton
A.A.
et al.  
SCA2 may present as levodopa-responsive parkinsonism
Mov. Disord.
 
2003
18
425
429
110
Shan
D.E.
Liu
R.S.
Sun
C.M.
Lee
S.J.
Liao
K.K.
Soong
B.W.
Presence of spinocerebellar ataxia type 2 gene mutation in a patient with apparently sporadic Parkinson's disease: clinical implications
Mov. Disord.
 
2004
19
1357
1360
111
Simon-Sanchez
J.
Hanson
M.
Singleton
A.
Hernandez
D.
McInerney
A.
Nussbaum
R.
Werner
J.
Gallardo
M.
Weiser
R.
Gwinn-Hardy
K.
et al.  
Analysis of SCA-2 and SCA-3 repeats in Parkinsonism: evidence of SCA-2 expansion in a family with autosomal dominant Parkinson's disease
Neurosci. Lett.
 
2005
382
191
194
112
Kim
J.M.
Hong
S.
Kim
G.P.
Choi
Y.J.
Kim
Y.K.
Park
S.S.
Kim
S.E.
Jeon
B.S.
Importance of low-range CAG expansion and CAA interruption in SCA2 Parkinsonism
Arch. Neurol.
 
2007
64
1510
1518
113
Modoni
A.
Contarino
M.F.
Bentivoglio
A.R.
Tabolacci
E.
Santoro
M.
Calcagni
M.L.
Tonali
P.A.
Neri
G.
Silvestri
G.
Prevalence of spinocerebellar ataxia type 2 mutation among Italian Parkinsonian patients
Mov. Disord.
 
2007
22
324
327
114
Charles
P.
Camuzat
A.
Benammar
N.
Sellal
F.
Destee
A.
Bonnet
A.M.
Lesage
S.
Le Ber
I.
Stevanin
G.
Durr
A.
et al.  
Are interrupted SCA2 CAG repeat expansions responsible for parkinsonism?
Neurology
 
2007
69
1970
1975
115
Socal
M.P.
Emmel
V.E.
Rieder
C.R.
Hilbig
A.
Saraiva-Pereira
M.L.
Jardim
L.B.
Intrafamilial variability of Parkinson phenotype in SCAs: novel cases due to SCA2 and SCA3 expansions
Parkinsonism Relat. Disord
 
2008
Epub ahead of print November 4, 2008
116
Furtado
S.
Payami
H.
Lockhart
P.J.
Hanson
M.
Nutt
J.G.
Singleton
A.A.
Singleton
A.
Bower
J.
Utti
R.J.
Bird
T.D.
et al.  
Profile of families with parkinsonism-predominant spinocerebellar ataxia type 2 (SCA2)
Mov. Disord.
 
2004
19
622
629
117
Lu
C.S.
Wu Chou
Y.H.
Kuo
P.C.
Chang
H.C.
Weng
Y.H.
The parkinsonian phenotype of spinocerebellar ataxia type 2
Arch. Neurol.
 
2004
61
35
38
118
Lim
S.W.
Zhao
Y.
Chua
E.
Law
H.Y.
Yuen
Y.
Pavanni
R.
Wong
M.C.
Ng
I.S.
Yoon
C.S.
Puong
K.Y.
et al.  
Genetic analysis of SCA2, 3 and 17 in idiopathic Parkinson's disease
Neurosci. Lett.
 
2006
403
11
14
119
Choudhry
S.
Mukerji
M.
Srivastava
A.K.
Jain
S.
Brahmachari
S.K.
CAG repeat instability at SCA2 locus: anchoring CAA interruptions and linked single nucleotide polymorphisms
Hum. Mol. Genet.
 
2001
10
2437
2446
120
Farrer
M.
Maraganore
D.M.
Lockhart
P.
Singleton
A.
Lesnick
T.G.
de Andrade
M.
West
A.
de Silva
R.
Hardy
J.
Hernandez
D.
alpha-Synuclein gene haplotypes are associated with Parkinson's disease
Hum. Mol. Genet.
 
2001
10
1847
1851
121
Izumi
Y.
Morino
H.
Oda
M.
Maruyama
H.
Udaka
F.
Kameyama
M.
Nakamura
S.
Kawakami
H.
Genetic studies in Parkinson's disease with an alpha-synuclein/NACP gene polymorphism in Japan
Neurosci. Lett.
 
2001
300
125
127
122
Holzmann
C.
Kruger
R.
Saecker
A.M.
Schmitt
I.
Schols
L.
Berger
K.
Riess
O.
Polymorphisms of the alpha-synuclein promoter: expression analyses and association studies in Parkinson's disease
J. Neural Transm.
 
2003
110
67
76
123
Mueller
J.C.
Fuchs
J.
Hofer
A.
Zimprich
A.
Lichtner
P.
Illig
T.
Berg
D.
Wullner
U.
Meitinger
T.
Gasser
T.
Multiple regions of alpha-synuclein are associated with Parkinson's disease
Ann. Neurol.
 
2005
57
535
541
124
Maraganore
D.M.
de Andrade
M.
Elbaz
A.
Farrer
M.J.
Ioannidis
J.P.
Kruger
R.
Rocca
W.A.
Schneider
N.K.
Lesnick
T.G.
Lincoln
S.J.
et al.  
Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease
JAMA
 
2006
296
661
670
125
Hadjigeorgiou
G.M.
Xiromerisiou
G.
Gourbali
V.
Aggelakis
K.
Scarmeas
N.
Papadimitriou
A.
Singleton
A.
Association of alpha-synuclein Rep1 polymorphism and Parkinson's disease: influence of Rep1 on age at onset
Mov. Disord.
 
2006
21
534
539
126
Mizuta
I.
Satake
W.
Nakabayashi
Y.
Ito
C.
Suzuki
S.
Momose
Y.
Nagai
Y.
Oka
A.
Inoko
H.
Fukae
J.
et al.  
Multiple candidate gene analysis identifies alpha-synuclein as a susceptibility gene for sporadic Parkinson's disease
Hum. Mol. Genet.
 
2006
15
1151
1158
127
Pals
P.
Lincoln
S.
Manning
J.
Heckman
M.
Skipper
L.
Hulihan
M.
Van den Broeck
M.
De Pooter
T.
Cras
P.
Crook
J.
et al.  
alpha-Synuclein promoter confers susceptibility to Parkinson's disease
Ann. Neurol.
 
2004
56
591
595
128
Tan
E.K.
Chai
A.
Teo
Y.Y.
Zhao
Y.
Tan
C.
Shen
H.
Chandran
V.R.
Teoh
M.L.
Yih
Y.
Pavanni
R.
et al.  
Alpha-synuclein haplotypes implicated in risk of Parkinson's disease
Neurology
 
2004
62
128
131
129
Chiba-Falek
O.
Nussbaum
R.L.
Effect of allelic variation at the NACP-Rep1 repeat upstream of the alpha-synuclein gene (SNCA) on transcription in a cell culture luciferase reporter system
Hum. Mol. Genet.
 
2001
10
3101
3109
130
Goris
A.
Williams-Gray
C.H.
Clark
G.R.
Foltynie
T.
Lewis
S.J.
Brown
J.
Ban
M.
Spillantini
M.G.
Compston
A.
Burn
D.J.
et al.  
Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson's disease
Ann. Neurol.
 
2007
62
145
153
131
Galpern
W.R.
Lang
A.E.
Interface between tauopathies and synucleinopathies: a tale of two proteins
Ann. Neurol.
 
2006
59
449
458
132
Brighina
L.
Frigerio
R.
Schneider
N.K.
Lesnick
T.G.
de Andrade
M.
Cunningham
J.M.
Farrer
M.J.
Lincoln
S.J.
Checkoway
H.
Rocca
W.A.
et al.  
Alpha-synuclein, pesticides, and Parkinson disease: a case-control study
Neurology
 
2008
70
1461
1469
133
Di Fonzo
A.
Wu-Chou
Y.H.
Lu
C.S.
van Doeselaar
M.
Simons
E.J.
Rohe
C.F.
Chang
H.C.
Chen
R.S.
Weng
Y.H.
Vanacore
N.
et al.  
A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan
Neurogenetics
 
2006
7
133
138
134
Fung
H.C.
Chen
C.M.
Hardy
J.
Singleton
A.B.
Wu
Y.R.
A common genetic factor for Parkinson disease in ethnic Chinese population in Taiwan
BMC Neurol.
 
2006
6
47
135
Farrer
M.J.
Stone
J.T.
Lin
C.H.
Dachsel
J.C.
Hulihan
M.M.
Haugarvoll
K.
Ross
O.A.
Wu
R.M.
Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia
Parkinsonism Relat. Disord.
 
2007
13
89
92
136
Tan
E.K.
Zhao
Y.
Skipper
L.
Tan
M.G.
Di Fonzo
A.
Sun
L.
Fook-Chong
S.
Tang
S.
Chua
E.
Yuen
Y.
et al.  
The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: genetic and functional evidence
Hum. Genet.
 
2007
120
857
863
137
Li
C.
Ting
Z.
Qin
X.
Ying
W.
Li
B.
Guo Qiang
L.
Jian Fang
M.
Jing
Z.
Jian Qing
D.
Sheng Di
C.
The prevalence of LRRK2 Gly2385Arg variant in Chinese Han population with Parkinson's disease
Mov. Disord.
 
2007
22
2439
2443
138
Funayama
M.
Li
Y.
Tomiyama
H.
Yoshino
H.
Imamichi
Y.
Yamamoto
M.
Murata
M.
Toda
T.
Mizuno
Y.
Hattori
N.
Leucine-rich repeat kinase 2 G2385R variant is a risk factor for Parkinson disease in Asian population
Neuroreport
 
2007
18
273
275
139
Chan
D.K.
Ng
P.W.
Mok
V.
Yeung
J.
Fang
Z.M.
Clarke
R.
Leung
E.
Wong
L.
LRRK2 Gly2385Arg mutation and clinical features in a Chinese population with early-onset Parkinson's disease compared to late-onset patients
J. Neural. Transm.
 
2008
115
1275
1277
140
An
X.K.
Peng
R.
Li
T.
Burgunder
J.M.
Wu
Y.
Chen
W.J.
Zhang
J.H.
Wang
Y.C.
Xu
Y.M.
Gou
Y.R.
et al.  
LRRK2 Gly2385Arg variant is a risk factor of Parkinson's disease among Han-Chinese from mainland China
Eur. J. Neurol.
 
2008
15
301
305
141
Choi
J.M.
Woo
M.S.
Ma
H.I.
Kang
S.Y.
Sung
Y.H.
Yong
S.W.
Chung
S.J.
Kim
J.S.
Shin
H.W.
Lyoo
C.H.
et al.  
Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease
Neurogenetics
 
2008
9
263
269
142
Tan
E.K.
Zhao
Y.
Tan
L.
Lim
H.Q.
Lee
J.
Yuen
Y.
Pavanni
R.
Wong
M.C.
Fook-Chong
S.
Liu
J.J.
Analysis of LRRK2 Gly2385Arg genetic variant in non-Chinese Asians
Mov. Disord.
 
2007
22
1816
1818
143
Tan
E.K.
Fook-Chong
S.
Yi
Z.
Comparing LRRK2 Gly2385Arg carriers with noncarriers
Mov. Disord.
 
2007
22
749
750
144
Tan
E.K.
Lee
J.
Chen
C.P.
Wong
M.C.
Zhao
Y.
Case control analysis of LRRK2 Gly2385Arg in Alzheimer's disease
Neurobiol. Aging
 
2007
Epub ahead of print August 24, 2007
145
Tan
E.K.
Lee
J.
Lim
H.Q.
Yuen
Y.
Zhao
Y.
Essential tremor and the common LRRK2 G2385R variant
Parkinsonism Relat. Disord.
 
2008
14
569
571
146
Lu
C.S.
Chang
H.C.
Weng
Y.H.
Chen
R.S.
Bonifati
V.
Wu-Chou
Y.H.
Analysis of the LRRK2 Gly2385Arg variant in primary dystonia and multiple system atrophy in Taiwan
Parkinsonism Relat. Disord.
 
2008
14
393
396
147
Lin
C.H.
Tzen
K.Y.
Yu
C.Y.
Tai
C.H.
Farrer
M.J.
Wu
R.M.
LRRK2 mutation in familial Parkinson's disease in a Taiwanese population: clinical, PET, and functional studies
J. Biomed. Sci.
 
2008
15
661
667
148
Ross
O.A.
Wu
Y.R.
Lee
M.C.
Funayama
M.
Chen
M.L.
Soto
A.I.
Mata
I.F.
Lee-Chen
G.J.
Chen
C.M.
Tang
M.
et al.  
Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease
Ann. Neurol.
 
2008
64
88
92
149
Lu
C.S.
Wu-Chou
Y.H.
van Doeselaar
M.
Simons
E.J.
Chang
H.C.
Breedveld
G.J.
Di Fonzo
A.
Chen
R.S.
Weng
Y.H.
Lai
S.C.
et al.  
The LRRK2 Arg1628Pro variant is a risk factor for Parkinson's disease in the Chinese population
Neurogenetics
 
2008
9
271
276
150
Tan
E.K.
Tan
L.C.
Lim
H.Q.
Li
R.
Tang
M.
Yih
Y.
Pavanni
R.
Prakash
K.M.
Fook-Chong
S.
Zhao
Y.
LRRK2 R1628P increases risk of Parkinson's disease: replication evidence
Hum. Genet.
 
2008
124
287
288
151
Tan
E.K.
Tang
M.
Tan
L.C.
Wu
Y.R.
Wu
R.M.
Ross
O.A.
Zhao
Y.
Lrrk2 R1628P in non-Chinese Asian races
Ann. Neurol.
 
2008
64
472
473
152
Aharon-Peretz
J.
Rosenbaum
H.
Gershoni-Baruch
R.
Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews
N. Engl. J. Med.
 
2004
351
1972
1977
153
Lwin
A.
Orvisky
E.
Goker-Alpan
O.
LaMarca
M.E.
Sidransky
E.
Glucocerebrosidase mutations in subjects with parkinsonism
Mol. Genet. Metab.
 
2004
81
70
73
154
Sato
C.
Morgan
A.
Lang
A.E.
Salehi-Rad
S.
Kawarai
T.
Meng
Y.
Ray
P.N.
Farrer
L.A.
St George-Hyslop
P.
Rogaeva
E.
Analysis of the glucocerebrosidase gene in Parkinson's disease
Mov. Disord.
 
2005
20
367
370
155
Zimran
A.
Neudorfer
O.
Elstein
D.
The glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews
N. Engl. J. Med.
 
2005
352
728
731
Author reply 728-31
156
Eblan
M.J.
Scholz
S.
Stubblefield
B.
Gutti
U.
Goker-Alpan
O.
Hruska
K.S.
Singleton
A.B.
Sidransky
E.
Glucocerebrosidase mutations are not found in association with LRRK2 G2019S in subjects with parkinsonism
Neurosci. Lett.
 
2006
404
163
165
157
Toft
M.
Pielsticker
L.
Ross
O.A.
Aasly
J.O.
Farrer
M.J.
Glucocerebrosidase gene mutations and Parkinson disease in the Norwegian population
Neurology
 
2006
66
415
417
158
Bras
J.
Paisan-Ruiz
C.
Guerreiro
R.
Ribeiro
M.H.
Morgadinho
A.
Januario
C.
Sidransky
E.
Oliveira
C.
Singleton
A.
Complete screening for glucocerebrosidase mutations in Parkinson disease patients from Portugal
Neurobiol. Aging
 
2007
Epub ahead of print December 19, 2007
159
Clark
L.N.
Ross
B.M.
Wang
Y.
Mejia-Santana
H.
Harris
J.
Louis
E.D.
Cote
L.J.
Andrews
H.
Fahn
S.
Waters
C.
et al.  
Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease
Neurology
 
2007
69
1270
1277
160
Wu
Y.R.
Chen
C.M.
Chao
C.Y.
Ro
L.S.
Lyu
R.K.
Chang
K.H.
Lee-Chen
G.J.
Glucocerebrosidase gene mutation is a risk factor for early onset of Parkinson disease among Taiwanese
J. Neurol. Neurosurg. Psychiatry
 
2007
78
977
979
161
Ziegler
S.G.
Eblan
M.J.
Gutti
U.
Hruska
K.S.
Stubblefield
B.K.
Goker-Alpan
O.
LaMarca
M.E.
Sidransky
E.
Glucocerebrosidase mutations in Chinese subjects from Taiwan with sporadic Parkinson disease
Mol. Genet. Metab.
 
2007
91
195
200
162
De Marco
E.V.
Annesi
G.
Tarantino
P.
Rocca
F.E.
Provenzano
G.
Civitelli
D.
Ciro Candiano
I.C.
Annesi
F.
Carrideo
S.
Condino
F.
et al.  
Glucocerebrosidase gene mutations are associated with Parkinson's disease in southern Italy
Mov. Disord.
 
2008
23
460
463
163
Gan-Or
Z.
Giladi
N.
Rozovski
U.
Shifrin
C.
Rosner
S.
Gurevich
T.
Bar-Shira
A.
Orr-Urtreger
A.
Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset
Neurology
 
2008
70
2277
2283
164
Nichols
W.C.
Pankratz
N.
Marek
D.K.
Pauciulo
M.W.
Elsaesser
V.E.
Halter
C.A.
Rudolph
A.
Wojcieszek
J.
Pfeiffer
R.F.
Foroud
T.
Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset
Neurology
 
2008
Epub ahead of print November 5, 2008
165
Spitz
M.
Rozenberg
R.
Pereira Lda
V.
Reis Barbosa
E.
Association between Parkinson's disease and glucocerebrosidase mutations in Brazil
Parkinsonism Relat. Disord.
 
2008
14
58
62
166
Socal
M.P.
Bock
H.
Michelin-Tirelli
K.
Hilbig
A.
Saraiva-Pereira
M.L.
Rieder
C.R.
Jardim
L.B.
Parkinson's disease and the heterozygous state for glucocerebrosidase mutations among Brazilians
Parkinsonism Relat. Disord
 
2008
Epub ahead of print March 19, 2008
167
Goker-Alpan
O.
Giasson
B.I.
Eblan
M.J.
Nguyen
J.
Hurtig
H.I.
Lee
V.M.
Trojanowski
J.Q.
Sidransky
E.
Glucocerebrosidase mutations are an important risk factor for Lewy body disorders
Neurology
 
2006
67
908
910
168
Mata
I.F.
Samii
A.
Schneer
S.H.
Roberts
J.W.
Griffith
A.
Leis
B.C.
Schellenberg
G.D.
Sidransky
E.
Bird
T.D.
Leverenz
J.B.
et al.  
Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders
Arch. Neurol.
 
2008
65
379
382
169
Farrer
M.J.
Williams
L.N.
Algom
A.A.
Kachergus
J.
Hulihan
M.M.
Ross
O.A.
Rajput
A.
Papapetropoulos
S.
Mash
D.C.
Dickson
D.W.
Glucosidase-beta variations and Lewy body disorders
Parkinsonism Relat. Disord
 
2008
Epub ahead of print September 29, 2008
170
Feany
M.B.
New genetic insights into Parkinson's disease
N. Engl. J. Med.
 
2004
351
1937
1940
171
Wong
K.
Sidransky
E.
Verma
A.
Mixon
T.
Sandberg
G.D.
Wakefield
L.K.
Morrison
A.
Lwin
A.
Colegial
C.
Allman
J.M.
et al.  
Neuropathology provides clues to the pathophysiology of Gaucher disease
Mol. Genet. Metab.
 
2004
82
192
207
172
Maraganore
D.M.
de Andrade
M.
Lesnick
T.G.
Strain
K.J.
Farrer
M.J.
Rocca
W.A.
Pant
P.V.
Frazer
K.A.
Cox
D.R.
Ballinger
D.G.
High-resolution whole-genome association study of Parkinson disease
Am. J. Hum. Genet.
 
2005
77
685
693
173
Fung
H.C.
Scholz
S.
Matarin
M.
Simon-Sanchez
J.
Hernandez
D.
Britton
A.
Gibbs
J.R.
Langefeld
C.
Stiegert
M.L.
Schymick
J.
et al.  
Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data
Lancet Neurol.
 
2006
5
911
916
174
Myers
R.H.
Considerations for genomewide association studies in Parkinson disease
Am. J. Hum. Genet.
 
2006
78
1081
1082
175
Evangelou
E.
Maraganore
D.M.
Ioannidis
J.P.
Meta-analysis in genome-wide association datasets: strategies and application in Parkinson disease
PLoS ONE
 
2007
2
e196
176
Pankratz
N.
Wilk
J.B.
Latourelle
J.C.
Destefano
A.L.
Halter
C.
Pugh
E.W.
Doheny
K.F.
Gusella
J.F.
Nichols
W.C.
Foroud
T.
et al.  
Genomewide association study for susceptibility genes contributing to familial Parkinson disease
Hum. Genet.
 
2009
124
593
605
177
Lesnick
T.G.
Sorenson
E.J.
Ahlskog
J.E.
Henley
J.R.
Shehadeh
L.
Papapetropoulos
S.
Maraganore
D.M.
Beyond Parkinson disease: amyotrophic lateral sclerosis and the axon guidance pathway
PLoS ONE
 
2008
3
e1449
178
Li
Y.
Rowland
C.
Xiromerisiou
G.
Lagier
R.J.
Schrodi
S.J.
Dradiotis
E.
Ross
D.
Bui
N.
Catanese
J.
Aggelakis
K.
et al.  
Neither replication nor simulation supports a role for the axon guidance pathway in the genetics of Parkinson's disease
PLoS ONE
 
2008
3
e2707