The development of next-generation sequencing technologies has allowed for the identification of several new genes and genetic factors in human genetics. Common results from the application of these technologies have revealed unexpected presentations for mutations in known disease genes. In this review, we summarize the major contributions of exome sequencing to the study of neurodegenerative disorders and other neurological conditions and discuss the interface between Mendelian and complex neurological diseases with a particular focus on pleiotropic events.

INTRODUCTION

The development of new technologies has revolutionized the field of genetics. We are now able to determine variation and structure at a genome-wide level, with base-pair resolution and to assess its impact on phenotypes in an unprecedented manner.

Genome-wide association studies (GWAS) have been essential to uncover common variability contributing to various complex disorders. Whole-exome and whole-genome sequencing have identified rare variants causing or imparting large effects both on Mendelian as well as on complex diseases. But perhaps more interesting is how the integration of these technologies is uncovering some unexpected results when molecular data are associated with clinical phenotypes and when previously overlooked biological processes become central pathobiological pathways in a disease.

TECHNOLOGICAL ADVANCES IN THE GENETICS OF DISEASE

Our understanding of the genetics underlying neurological disease has often been based on the development and application of new technologies. Perhaps the first example is how genetic linkage analyses of large pedigrees enabled the finding of several causative mutations underlying familial forms of disease. Case–control association studies on the other hand, which compared frequencies of genotypes in genes based on a priori biological hypotheses, did not have the same success for non-familial disorders. New loci for these common forms of disease have recently been found by GWAS where variation, distributed across the whole genome, is compared between thousands of cases and thousands of controls (1). For these forms of disease success clearly arrived when we were able to survey across the genome without the bias of biological plausibility. Thus, technological advances have allowed for the identification of very rare causative mutations underlying Mendelian forms of disease—through linkage analyses—and of common variants with low effects contributing to the susceptibility of late-onset and ‘sporadic’ disorders—through GWAS. However, limitations to these two approaches remain: linkage analyses are unable to adequately test variants that do not impart a very strong effect on disease, and GWAS is only suitable for variability that is relatively common in the general population. We are now able to test these types of variation by using whole-exome and other sequencing approaches (2,3).

WE ARE GETTING WHAT WE PAID FOR

Exome sequencing is not only allowing for the quick identification of many genes as the cause of several diseases, it is also uncovering new risk factors for complex disorders. The application of this recently developed sequencing technology to neurological diseases is no exception and many examples of novel genes being associated with these disorders can now be found in the literature (Table 1).

Table 1.

Examples of novel genes recently found to be associated with neurodegenerative diseases by the use of exome sequencing

Disease Gene Mutation(s) Effect on disease Refs. 
Parkinson's disease VPS35 Heterozygous p.Asp620Asn Causative (4,5
Alzheimer's disease TREM2 Heterozygous p.R47H Increased risk (OR > 3) (6,7
Alzheimer's disease SORL1 Heterozygous missense and nonsense Potentially causative (8
Hereditary diffuse leukoencephalopathy with spheroids CSF1R Heterozygous missense, insertions and deletions all affecting the protein tyrosine kinase domain Causative (9
Amyotrophic lateral sclerosis PFN1 Heterozygous missense Causative (10
Autosomal-recessive cerebellar ataxia with spasticity GBA2 Homozygous missense and nonsense Causative (11
Disease Gene Mutation(s) Effect on disease Refs. 
Parkinson's disease VPS35 Heterozygous p.Asp620Asn Causative (4,5
Alzheimer's disease TREM2 Heterozygous p.R47H Increased risk (OR > 3) (6,7
Alzheimer's disease SORL1 Heterozygous missense and nonsense Potentially causative (8
Hereditary diffuse leukoencephalopathy with spheroids CSF1R Heterozygous missense, insertions and deletions all affecting the protein tyrosine kinase domain Causative (9
Amyotrophic lateral sclerosis PFN1 Heterozygous missense Causative (10
Autosomal-recessive cerebellar ataxia with spasticity GBA2 Homozygous missense and nonsense Causative (11

Most causative novel genes have been identified in families where a specific phenotype segregates, either presenting a dominant or recessive pattern of inheritance. In the case of recessive diseases, the results obtained by exome sequencing are often guided by autozygosity mapping and in the case of dominant diseases, by genetic linkage analyses (12).

The number of findings is expected to increase as more samples; more funding and more collaborations are put in place. Several large projects are currently underway including several national and international collaborations. Probably, the largest of these projects is the Alzheimer's Disease Sequencing Project (ADSP - https://www.niagads.org/adsp/content/home), a joint effort between the National Human Genome Research Institute and the National Institute on Aging, which was one of the first projects launched under the $130 million National Alzheimer's Project, that started in 2012.

The democratization of massively parallel sequencing, and in particular of exome sequencing, has allowed for the identification (and will likely continue to identify) of an enormous number of novel genetic defects causing different diseases (Table 1). Even though the observation that mutations in the same gene can affect distinct clinical phenotypes has been a well-known and studied concept in molecular genetics (13), this avalanche of data resulting from the first era of exome sequencing has revealed novel connections between phenotypes that can help us to better understand the pathobiology of different neurological diseases. To consider these pleiotropic events, we will firstly discuss different instances where variants present in the same genes were found to be involved in different phenotypes and, secondly, we will focus on more specific cases where same-gene variants have been shown to exert different effects on diseases, depending on the way the variant is inherited.

VARIANTS IN THE SAME GENES CAUSING DIFFERENT PHENOTYPES

The definition of ‘different phenotypes’ can be rather difficult. One illustrative example is the overlap between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis: based on clinical, genetic and epidemiological data, these two previously thought of as completely independent entities, seem to be on opposite ends of a spectrum of disease, characterized pathologically by the presence of TDP-43 positive inclusions throughout the central nervous system (1416). Adding to this clinical and neuropathological overlap is the recent molecular finding of hexanucleotide intronic expansions in C9ORF72 as the cause of both FTD and ALS. It is currently not known why individuals with apparently the same genetic alteration develop either ALS or FTD (17,18). One possibility is that different expansion sizes are associated with different phenotypes; a hypothesis that has proved very difficult to test since the size of each mutated allele is difficult to assess.

Examples like the C9ORF72 involvement in two clinically distinct entities raise questions about the best way to define diseases, particularly regarding the weight that should be put on the molecular findings and on the relationship between these findings and the neuropathological signatures associated with each disease. From the examples given in Table 2, it is difficult to reach definite conclusions for most cases: for ATP13A2, no pathological analysis of Kufor Rakeb brains has been performed yet; the Alzheimer's disease case with a CADASIL-associated mutation is still alive; and for GRN no pathological assessment of the NCL homozygous cases was done, although mice present with typical NCL lesions. However, for VCP, it has been clinically and neuropathologically demonstrated that mutations in this gene are responsible for cases diagnosed with either IBMPFD or ALS (19).

Table 2.

Examples of mutations in the same genes causing different diseases, highlighting the role of NGS in uncovering pleiotropic events in neurodegenerative disorders

Gene Initially described in disease(s) Type of mutation Also found in Type of mutation Refs. 
ATP13A2* Kufor Rakeb syndrome (KRS, OMIM #606693) Frameshift homozygous Neuronal ceroid-lipofuscinosis (NCL) Missense homozygous (20,21
NOTCH3* Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL, OMIM #125310) Missense heterozygous changing a cysteine residue in the protein Alzheimer's disease (AD, OMIM #104300) Missense heterozygous changing a cysteine residue in the protein (22,23
C9ORF72 Frontotemporal dementia (FTD, OMIM #600274) and/or amyotrophic lateral sclerosis (ALS, OMIM #105400) GGGGCC hexanucleotide intronic expansion   (17,18
SQSTM1 Paget disease of the bone (PDB, OMIM #602080) Missense heterozygous; frameshift; affecting splice site FTD and ALS Missense heterozygous; affecting splice site (2427
GRN* FTD Heterozygous null Neuronal ceroid lipofuscinosis (CLN11, OMIM #614706) Homozygous null (2830
VCP* Inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD, OMIM #167320) Heterozygous missense ALS and hereditary spastic paraplegia Heterozygous missense (19,31,32
PLA2G6 Neurodegeneration with Brain Iron Accumulation 2A and 2B and Karak Syndrome (INAD, NBIA2A, OMIM # 256600 and NBIA2B, OMIM # 610217) Missense, nonsense, splice-site, deletions, large intragenic deletions, homozygous or compound heterozygous Adult-onset dystonia-parkinsonism (PARK14, OMIM 612953) Homozygous and compound heterozygous missense and frameshift (33,34
PSEN1 AD Missense, small insertions, heterozygous Acne inversa (ACNINV3, OMIM #613737) Frameshift deletion (35,36
TRPV4 Scapuloperoneal spinal muscular atrophy (SPSMA, OMIM #181405) Missense heterozygous Charcot-Marie-Tooth disease type 2C (HMSN2C, #606071) Missense heterozygous (37
TPP1* Late-infantile Neuronal Ceroid Lipofuscinosis 2 (CLN2, OMIM #204500) Missense, nonsense, splice-site affecting, deletions, insertions and deletion–insertion homozygous or compound heterozygous Autosomal recessive spinocerebellar ataxia 7 (SCAR7, OMIM %609270) Compound heterozygous (3840
Gene Initially described in disease(s) Type of mutation Also found in Type of mutation Refs. 
ATP13A2* Kufor Rakeb syndrome (KRS, OMIM #606693) Frameshift homozygous Neuronal ceroid-lipofuscinosis (NCL) Missense homozygous (20,21
NOTCH3* Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL, OMIM #125310) Missense heterozygous changing a cysteine residue in the protein Alzheimer's disease (AD, OMIM #104300) Missense heterozygous changing a cysteine residue in the protein (22,23
C9ORF72 Frontotemporal dementia (FTD, OMIM #600274) and/or amyotrophic lateral sclerosis (ALS, OMIM #105400) GGGGCC hexanucleotide intronic expansion   (17,18
SQSTM1 Paget disease of the bone (PDB, OMIM #602080) Missense heterozygous; frameshift; affecting splice site FTD and ALS Missense heterozygous; affecting splice site (2427
GRN* FTD Heterozygous null Neuronal ceroid lipofuscinosis (CLN11, OMIM #614706) Homozygous null (2830
VCP* Inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD, OMIM #167320) Heterozygous missense ALS and hereditary spastic paraplegia Heterozygous missense (19,31,32
PLA2G6 Neurodegeneration with Brain Iron Accumulation 2A and 2B and Karak Syndrome (INAD, NBIA2A, OMIM # 256600 and NBIA2B, OMIM # 610217) Missense, nonsense, splice-site, deletions, large intragenic deletions, homozygous or compound heterozygous Adult-onset dystonia-parkinsonism (PARK14, OMIM 612953) Homozygous and compound heterozygous missense and frameshift (33,34
PSEN1 AD Missense, small insertions, heterozygous Acne inversa (ACNINV3, OMIM #613737) Frameshift deletion (35,36
TRPV4 Scapuloperoneal spinal muscular atrophy (SPSMA, OMIM #181405) Missense heterozygous Charcot-Marie-Tooth disease type 2C (HMSN2C, #606071) Missense heterozygous (37
TPP1* Late-infantile Neuronal Ceroid Lipofuscinosis 2 (CLN2, OMIM #204500) Missense, nonsense, splice-site affecting, deletions, insertions and deletion–insertion homozygous or compound heterozygous Autosomal recessive spinocerebellar ataxia 7 (SCAR7, OMIM %609270) Compound heterozygous (3840

*Second association found by exome sequencing. Refs., references associated with the original descriptions in the different diseases.

In line with the aforementioned spectrum of FTD-ALS disease, these results expand even more the range of overlap by including an association of ALS with bone dysfunction and myopathy. At the same time, these results point towards the involvement of cellular protein degradation processes in the molecular patholog of ALS. The involvement of such pathobiological pathways in ALS can also be substantiated by the recent findings of SQSTM1 (encoding the p62 protein, a multifunctional protein that binds ubiquitin and is one of the best-known autophagic substrates) (41) mutations both in ALS and FTD (24,25).

Many other atypical phenotypical presentations are suggested in the literature, particularly for different dementias, for example PSEN1 mutations were found in FTD cases (42,43) and a nonsense mutation in PRNP was associated with clinical and neuropathological features of AD (44).

Although these overlaps between different clinical entities can generate difficulties in the establishment of definitive diagnoses, the assessment of mixed cohorts has also revealed interesting genetic findings: high throughput deep sequencing identified several GRN and MAPT mutations in AD clinical cohorts (possibly due to misdiagnoses) (45), a genome-wide analysis uncovered several risk loci with shared effects on five psychiatric disorders (46) and the joint analysis of multisystem proteinopathy cases reflecting the expanded phenotype and proteinaceous pathology characterizing diseases as IBM, FTD, ALS and PDB has allowed for the identification of causative mutations in hnRNPA2B1 and hnRNPA1 (47).

It is also possible that the relative abundance of pleiotropic effects being found by exome sequencing results from the difficulty in interpreting the pathogenic impact of some variants identified through NGS. High throughput techniques have shown that each individual carries a large number of genomic variations of unclear significance and for some of these variations, especially if found in isolated patients and in the absence of functional studies, the establishment of their pathogenicity in relation to a specific phenotype may be extremely problematic. As more and more samples are being sequenced, we see that variants previously thought to be pathogenic are being found in healthy individuals, challenging the definition of causality and the interpretation of NGS results.

The establishment of pathogenicity to variants identified through NGS is far from being a straightforward process, and it is currently posing as a potential confounder for the identification of true pleiotropic events and requiring new tools to adequately assess this issue.

VARIANTS IN THE SAME GENE CAN CAUSE A RARE EARLY-ONSET SEVERE DISEASE AND MODULATE THE RISK FOR A LATE-ONSET COMMON DISEASE

One result we previously predicted is the finding of pairs of diseases previously thought to be unrelated and that are influenced by different types of genetic variation in the same gene (48): one disease is usually severe, has an early onset, and is caused by homozygous loss-of-function mutations, while the other is a late-onset disease with increased susceptibility caused by heterozygous (probably with partial loss-of-function) variants in the same gene (Table 3).

Table 3.

Examples of homozygous/heterozygous variants in the same gene causing a severe early-onset disease and increasing the risk for a different late-onset disease

Gene Homozygous mutations cause Refs. Heterozygous variants increase risk for Refs. 
TREM2 Nasu-Hakola and FTD-like syndrome without bone disease (49,50Alzheimer's disease (6,7
GBA Gaucher's disease (51Parkinson's disease (52
Gene Homozygous mutations cause Refs. Heterozygous variants increase risk for Refs. 
TREM2 Nasu-Hakola and FTD-like syndrome without bone disease (49,50Alzheimer's disease (6,7
GBA Gaucher's disease (51Parkinson's disease (52

Refs., references.

Usually mutations in one gene cause specific phenotypes either in the heterozygous or in the homozygous state, but generally not in both. In autosomal recessive diseases, heterozygous individuals are usually healthy. In autosomal dominant disorders, the allele frequency for the mutation is low, thus homozygous individuals are very rare, with the exception of highly inbred populations. When observed, these homozygous cases are usually very similar to the heterozygous affected family members [Huntington disease (53), Parkinson's disease (54), Creutzfeldt-Jakob disease (55)] or have a more severe form of the same phenotype (Spinocerebellar Ataxia-2, -3 and -6, for example) (5659).

The occurrence in the same locus of genetic variation with different modes of inheritance imparting different effects on different diseases can partially be explained by natural selection: homozygous loss of function mutations cause early-onset disorders and many individuals with these mutations die before reaching reproductive age, contributing to the rare frequency of the disease and of the mutations. On the other hand, heterozygous variants confer risk to a disorder with an onset usually occurring beyond reproductive age, making these variants and diseases more common in the population.

Homozygous mutations in TREM2 were originally found to be the cause of Nasu-Hakola disease (also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy), a rare autosomal recessive form of dementia presenting with pain and swelling of wrists and/or ankles due to bone cysts and usually followed by bone fractures (49). Patients usually die in the fourth decade of life presenting the later features of the disease that resemble those of AD or FTD. The same type of mutations (and in some cases the same exact mutations) have been described in patients presenting with frontotemporal dementia, but with no associated bone phenotypes (50,60). More recently, a rare heterozygous variant (p.R47H) was associated with an increased risk of AD (6,7). TREM2 is a membrane protein that forms a receptor–signalling complex with TYROBP (also known as DAP-12) and works to activate immune responses in different cells from the myeloid lineage, like macrophages and dendritic cells. It is thought to have an anti-inflammatory role in the brain (49). In AD, loss-of-function or partial loss-of-function mutations in the gene are expected to alter inflammatory processes and lead to a decreased ability of clearing amyloid plaques, with a consequent increase in cell death and cognitive decline. Common variation in the TREM2 locus has also been associated by GWAS with C-reactive protein levels (61) and potential associations of p.R47H with FTD, ALS and Parkinson's disease have also been reported (6265), suggesting a potential role for TREM2 across different neurodegenerative disorders.

In a similar fashion, homozygous mutations in the gene coding for the glucocerebrosidase (GBA) enzyme cause Gaucher's disease, a lysosomal storage disease characterized by the accumulation of GBAs (51), while heterozygous variants in GBA have been associated with an increased risk of PD (52), DLB (66) and PD with dementia (67).

These findings have confirmed the central role of inflammation and lysosomal pathways in AD and PD, respectively.

Also interesting to note are the associations between heterozygous variants in autosomal recessive PD loci and different pathologies. Homozygous mutations in PARK2 (encoding parkin, an E3 ubiquitin ligase) are known to cause early-onset forms of Parkinson disease (68) and the association of heterozygous variants with an increased risk of PD has long been debated. More recently, PARK2 somatic mutations have been associated with different types of cancer (69), suggesting that germline mutations in PARK2 cause PD and somatic mutations contribute to cancer (for a review see Plun-Favreau et al.) (70). Additionally, genome-wide analysis of rare copy number variants identified PARK2 as a candidate gene for attention-deficit/hyperactivity disorder and GWAS have found significant associations between common variability in this locus with lumbar disc degeneration (in a meta-analysis of northern Europeans) (71), ageing (by performing linkage and association in large Amish kindreds) (72), pancreatic cancer in the Japanese population (73) and metabolite levels (74). The fact that PARK2 is embedded in a common fragile site (FRA6R) and, consequently, is particularly prone to breaks, may explain the frequent occurrence of PARK2 gross mutations like deletions in cancer cells and the association of copy number variants with attention-deficit/hyperactivity disorder (75). However, it is difficult to anticipate a related mechanism for the associations established with common point variability in the locus, especially since similar associations have been identified for other PARK loci: by GWAS, PARK7 has been associated with ulcerative colitis (76) and celiac disease (77), while PLA2G6 has been associated with susceptibility to melanoma (78) and cutaneous nevi (79,80) (high melanocytic nevi count is the strongest known risk factor for cutaneous melanoma). Interestingly, LRRK2 has also been associated with inflammatory bowel disease, Crohn's disease and leprosy (8184).

POSSIBLE MECHANISMS FOR COMPLEX ASSOCIATIONS BETWEEN MOLECULAR FINDINGS AND PHENOTYPES

While revealing this increasing complexity (that can be considered to challenge the basis of Mendelian genetics), NGS techniques are also providing some relevant insights into the mechanisms underlying such complexity. One example previously mentioned is the possibility that different expansion sizes of C9ORF72 are related to either a phenotype of FTD or ALS. However, besides this more obvious possible correlation between different types of mutations and distinct phenotypes, other mechanisms can be involved and these include: oligogenic or polygenic inheritance, variants in distinct genes acting as phenotypic modifiers of a monogenic disorder, different genetic background, gene–gene interactions, differential expression levels in different cell types, environmental factors or epigenetic effects. All of which will require much larger and deeply studied data sets to be tested on.

CONCLUSION

Results from exome sequencing analyses have reinforced the notion that some neurodegenerative diseases are part of pathological spectrums arising from common molecular processes. In the context of late-onset diseases, and in particular diseases with a long preclinical phase, it is not surprising that there is substantial clinical heterogeneity given the potential for influence of different factors (including genetic and environmental) from the inception of the process to phenotypic presentation. This would be more obvious if the genes mutated were involved with repair or response to an insult—the end point would be determined by what the initial problem was and where it started.

These commonalities observed between different diseases cannot only be seen in the form of pure pleiotropic genetic effects but also, and perhaps more interestingly, when variants in the same gene but with different patterns of inheritance cause a severe early-onset disease and modulate the risk for a more common and less severe late-onset disorder.

Although extraordinary advances are being made by the application of exome sequencing to the study of neurological diseases, it is also important to mention that at least part of the genetic lesions contributing to these diseases will not be amenable to be found by exome or even genome sequencing. The large intronic hexanucleotide expansion in C9ORF72 is a clear example in neurological diseases but examples from other diseases are also arising, like the large VNTR in MUC1 causing medullary cystic kidney disease type 1 (85).

Clearly some of these results will help clinicians understand the co-occurrence of clinical phenotypes in patients, as well as point to wider genetic screens when the obvious candidate genes are negative for mutations, and to potential druggable targets. The latter is already evident from the recent programmes that several drug companies have started on inflammation and associated processes for Alzheimer's disease, following the identification of TREM2 as a risk gene for this disorder.

In summary, results showing genetically overlapping diseases have clear implications for the clinical diagnoses and follow-up of patients, but are also of great importance to uncover the molecular mechanisms underlying these pathologies.

Conflict of Interest statement. None declared.

FUNDING

The authors' work is supported by the Alzheimer's Research UK and by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium (UKPDC) whose members are from the UCL/Institute of Neurology, the University of Sheffield and the MRC Protein Phosphorylation Unit at the University of Dundee. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust/MRC.

REFERENCES

1
Manolio
T.A.
Collins
F.S.
Cox
N.J.
Goldstein
D.B.
Hindorff
L.A.
Hunter
D.J.
McCarthy
M.I.
Ramos
E.M.
Cardon
L.R.
Chakravarti
A.
et al.  
Finding the missing heritability of complex diseases
Nature
 
2009
461
747
753
2
Hardy
J.
Singleton
A.
Genomewide association studies and human disease
N. Engl. J. Med.
 
2009
360
1759
1768
3
Singleton
A.B.
Hardy
J.
Traynor
B.J.
Houlden
H.
Towards a complete resolution of the genetic architecture of disease
Trends Genet.
 
2010
26
438
442
4
Zimprich
A.
Benet-Pages
A.
Struhal
W.
Graf
E.
Eck
S.H.
Offman
M.N.
Haubenberger
D.
Spielberger
S.
Schulte
E.C.
Lichtner
P.
et al.  
A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease
Am. J. Hum. Genet.
 
2011
89
168
175
5
Vilarino-Guell
C.
Wider
C.
Ross
O.A.
Dachsel
J.C.
Kachergus
J.M.
Lincoln
S.J.
Soto-Ortolaza
A.I.
Cobb
S.A.
Wilhoite
G.J.
Bacon
J.A.
et al.  
VPS35 mutations in Parkinson disease
Am. J. Hum. Genet.
 
2011
89
162
167
6
Guerreiro
R.
Wojtas
A.
Bras
J.
Carrasquillo
M.
Rogaeva
E.
Majounie
E.
Cruchaga
C.
Sassi
C.
Kauwe
J.S.
Younkin
S.
et al.  
TREM2 variants in Alzheimer's disease
N. Engl. J. Med
 
2012
368
117
127
7
Jonsson
T.
Stefansson
H.
Steinberg
S.
Jonsdottir
I.
Jonsson
P.V.
Snaedal
J.
Bjornsson
S.
Huttenlocher
J.
Levey
A.I.
Lah
J.J.
et al.  
Variant of TREM2 associated with the risk of Alzheimer's disease
N. Engl. J. Med.
 
2013
368
107
116
8
Pottier
C.
Hannequin
D.
Coutant
S.
Rovelet-Lecrux
A.
Wallon
D.
Rousseau
S.
Legallic
S.
Paquet
C.
Bombois
S.
Pariente
J.
et al.  
High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease
Mol. Psychiatry
 
2012
17
875
879
9
Rademakers
R.
Baker
M.
Nicholson
A.M.
Rutherford
N.J.
Finch
N.
Soto-Ortolaza
A.
Lash
J.
Wider
C.
Wojtas
A.
DeJesus-Hernandez
M.
et al.  
Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids
Nat. Genet.
 
2012
44
200
205
10
Wu
C.H.
Fallini
C.
Ticozzi
N.
Keagle
P.J.
Sapp
P.C.
Piotrowska
K.
Lowe
P.
Koppers
M.
McKenna-Yasek
D.
Baron
D.M.
et al.  
Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis
Nature
 
2012
488
499
503
11
Hammer
M.B.
Eleuch-Fayache
G.
Schottlaender
L.V.
Nehdi
H.
Gibbs
J.R.
Arepalli
S.K.
Chong
S.B.
Hernandez
D.G.
Sailer
A.
Liu
G.
et al.  
Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity
Am. J. Hum. Genet.
 
2013
92
245
251
12
Bras
J.
Guerreiro
R.
Hardy
J.
Use of next-generation sequencing and other whole-genome strategies to dissect neurological disease
Nat. Rev. Neurosci.
 
2012
13
453
464
13
Stearns
F.W.
One hundred years of pleiotropy: a retrospective
Genetics
 
2010
186
767
773
14
Lillo
P.
Hodges
J.R.
Frontotemporal dementia and motor neurone disease: overlapping clinic-pathological disorders
J. Clin. Neurosci.
 
2009
16
1131
1135
15
Neumann
M.
Sampathu
D.M.
Kwong
L.K.
Truax
A.C.
Micsenyi
M.C.
Chou
T.T.
Bruce
J.
Schuck
T.
Grossman
M.
Clark
C.M.
et al.  
Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Science
 
2006
314
130
133
16
Geser
F.
Lee
V.M.
Trojanowski
J.Q.
Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: a spectrum of TDP-43 proteinopathies
Neuropathology
 
2010
30
103
112
17
Renton
A.E.
Majounie
E.
Waite
A.
Simon-Sanchez
J.
Rollinson
S.
Gibbs
J.R.
Schymick
J.C.
Laaksovirta
H.
van Swieten
J.C.
Myllykangas
L.
et al.  
A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD
Neuron
 
2011
72
257
268
18
DeJesus-Hernandez
M.
Mackenzie
I.R.
Boeve
B.F.
Boxer
A.L.
Baker
M.
Rutherford
N.J.
Nicholson
A.M.
Finch
N.A.
Flynn
H.
Adamson
J.
et al.  
Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
Neuron
 
2011
72
245
256
19
Johnson
J.O.
Mandrioli
J.
Benatar
M.
Abramzon
Y.
Van Deerlin
V.M.
Trojanowski
J.Q.
Gibbs
J.R.
Brunetti
M.
Gronka
S.
Wuu
J.
et al.  
Exome sequencing reveals VCP mutations as a cause of familial ALS
Neuron
 
2010
68
857
864
20
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. Genet.
 
2006
38
1184
1191
21
Bras
J.
Verloes
A.
Schneider
S.A.
Mole
S.E.
Guerreiro
R.J.
Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis
Hum. Mol. Genet.
 
2012
21
2646
2650
22
Joutel
A.
Corpechot
C.
Ducros
A.
Vahedi
K.
Chabriat
H.
Mouton
P.
Alamowitch
S.
Domenga
V.
Cecillion
M.
Marechal
E.
et al.  
Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia
Nature
 
1996
383
707
710
23
Guerreiro
R.J.
Lohmann
E.
Kinsella
E.
Bras
J.M.
Luu
N.
Gurunlian
N.
Dursun
B.
Bilgic
B.
Santana
I.
Hanagasi
H.
et al.  
Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease
Neurobiol. Aging
 
2012
33
1008 e1017
1023
24
Rubino
E.
Rainero
I.
Chio
A.
Rogaeva
E.
Galimberti
D.
Fenoglio
P.
Grinberg
Y.
Isaia
G.
Calvo
A.
Gentile
S.
et al.  
SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Neurology
 
2012
79
1556
1562
25
Le Ber
I.
Camuzat
A.
Guerreiro
R.
Bouya-Ahmed
K.
Bras
J.
Nicolas
G.
Gabelle
A.
Didic
M.
De Septenville
A.
Millecamps
S.
et al.  
SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis
JAMA Neurol.
 
2013
70
1403
1410
26
Laurin
N.
Brown
J.P.
Morissette
J.
Raymond
V.
Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone
Am. J. Hum. Genet.
 
2002
70
1582
1588
27
Fecto
F.
Yan
J.
Vemula
S.P.
Liu
E.
Yang
Y.
Chen
W.
Zheng
J.G.
Shi
Y.
Siddique
N.
Arrat
H.
et al.  
SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis
Arch. Neurol.
 
2011
68
1440
1446
28
Cruts
M.
Gijselinck
I.
van der Zee
J.
Engelborghs
S.
Wils
H.
Pirici
D.
Rademakers
R.
Vandenberghe
R.
Dermaut
B.
Martin
J.J.
et al.  
Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21
Nature
 
2006
442
920
924
29
Baker
M.
Mackenzie
I.R.
Pickering-Brown
S.M.
Gass
J.
Rademakers
R.
Lindholm
C.
Snowden
J.
Adamson
J.
Sadovnick
A.D.
Rollinson
S.
et al.  
Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17
Nature
 
2006
442
916
919
30
Smith
K.R.
Damiano
J.
Franceschetti
S.
Carpenter
S.
Canafoglia
L.
Morbin
M.
Rossi
G.
Pareyson
D.
Mole
S.E.
Staropoli
J.F.
et al.  
Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage
Am. J. Hum. Genet.
 
2012
90
1102
1107
31
Watts
G.D.
Wymer
J.
Kovach
M.J.
Mehta
S.G.
Mumm
S.
Darvish
D.
Pestronk
A.
Whyte
M.P.
Kimonis
V.E.
Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein
Nat. Genet.
 
2004
36
377
381
32
de Bot
S.T.
Schelhaas
H.J.
Kamsteeg
E.J.
van de Warrenburg
B.P.
Hereditary spastic paraplegia caused by a mutation in the VCP gene
Brain
 
2012
135
e223
author reply e224
33
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.
 
2009
65
19
23
34
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
35
Wang
B.
Yang
W.
Wen
W.
Sun
J.
Su
B.
Liu
B.
Ma
D.
Lv
D.
Wen
Y.
Qu
T.
et al.  
Gamma-secretase gene mutations in familial acne inversa
Science
 
2010
330
1065
36
Sherrington
R.
Rogaev
E.I.
Liang
Y.
Rogaeva
E.A.
Levesque
G.
Ikeda
M.
Chi
H.
Lin
C.
Li
G.
Holman
K.
et al.  
Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease
Nature
 
1995
375
754
760
37
Deng
H.X.
Klein
C.J.
Yan
J.
Shi
Y.
Wu
Y.
Fecto
F.
Yau
H.J.
Yang
Y.
Zhai
H.
Siddique
N.
et al.  
Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4
Nat. Genet.
 
2010
42
165
169
38
Sleat
D.E.
Donnelly
R.J.
Lackland
H.
Liu
C.G.
Sohar
I.
Pullarkat
R.K.
Lobel
P.
Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis
Science
 
1997
277
1802
1805
39
Sun
Y.
Almomani
R.
Breedveld
G.J.
Santen
G.W.
Aten
E.
Lefeber
D.J.
Hoff
J.I.
Brusse
E.
Verheijen
F.W.
Verdijk
R.M.
et al.  
Autosomal Recessive Spinocerebellar Ataxia 7 (SCAR7) is caused by variants in TPP1, the Gene Involved in Classic Late-Infantile Neuronal Ceroid Lipofuscinosis 2 Disease (CLN2 Disease)
Hum. Mutat
 
2013
34
706
713
40
Kousi
M.
Lehesjoki
A.E.
Mole
S.E.
Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses
Hum. Mutat.
 
2012
33
42
63
41
Sahani
M.H.
Itakura
E.
Mizushima
N.
Expression of the autophagy substrate SQSTM1/p62 is restored during prolonged starvation depending on transcriptional upregulation and autophagy-derived amino acids
Autophagy
 
2014
10
431
441
42
Rippon
G.A.
Crook
R.
Baker
M.
Halvorsen
E.
Chin
S.
Hutton
M.
Houlden
H.
Hardy
J.
Lynch
T.
Presenilin 1 mutation in an African American family presenting with atypical Alzheimer dementia
Arch. Neurol.
 
2003
60
884
888
43
Raux
G.
Gantier
R.
Thomas-Anterion
C.
Boulliat
J.
Verpillat
P.
Hannequin
D.
Brice
A.
Frebourg
T.
Campion
D.
Dementia with prominent frontotemporal features associated with L113P presenilin 1 mutation
Neurol.
 
2000
55
1577
1578
44
Jayadev
S.
Nochlin
D.
Poorkaj
P.
Steinbart
E.J.
Mastrianni
J.A.
Montine
T.J.
Ghetti
B.
Schellenberg
G.D.
Bird
T.D.
Leverenz
J.B.
Familial prion disease with Alzheimer disease-like tau pathology and clinical phenotype
Ann. Neurol.
 
2011
69
712
720
45
Cruchaga
C.
Haller
G.
Chakraverty
S.
Mayo
K.
Vallania
F.L.
Mitra
R.D.
Faber
K.
Williamson
J.
Bird
T.
Diaz-Arrastia
R.
et al.  
Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families
PLoS One
 
2012
7
e31039
46
Cross-Disorder Group of the Psychiatric Genomics Consortium
Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis
Lancet
 
2013
381
1371
1379
47
Kim
H.J.
Kim
N.C.
Wang
Y.D.
Scarborough
E.A.
Moore
J.
Diaz
Z.
Maclea
K.S.
Freibaum
B.
Li
S.
Molliex
A.
et al.  
Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS
Nature
 
2013
495
467
473
48
Singleton
A.
Hardy
J.
A generalizable hypothesis for the genetic architecture of disease: pleomorphic risk loci
Hum. Mol. Genet.
 
2011
20
R158
R162
49
Paloneva
J.
Manninen
T.
Christman
G.
Hovanes
K.
Mandelin
J.
Adolfsson
R.
Bianchin
M.
Bird
T.
Miranda
R.
Salmaggi
A.
et al.  
Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype
Am. J. Hum. Genet.
 
2002
71
656
662
50
Guerreiro
R.J.
Lohmann
E.
Bras
J.M.
Gibbs
J.R.
Rohrer
J.D.
Gurunlian
N.
Dursun
B.
Bilgic
B.
Hanagasi
H.
Gurvit
H.
et al.  
Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement
Arch. Neurol.
 
2012
70
78
84
51
Tsuji
S.
Choudary
P.V.
Martin
B.M.
Stubblefield
B.K.
Mayor
J.A.
Barranger
J.A.
Ginns
E.I.
A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher's disease
N. Engl. J. Med.
 
1987
316
570
575
52
Sidransky
E.
Nalls
M.A.
Aasly
J.O.
Aharon-Peretz
J.
Annesi
G.
Barbosa
E.R.
Bar-Shira
A.
Berg
D.
Bras
J.
Brice
A.
et al.  
Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease
N. Engl. J. Med.
 
2009
361
1651
1661
53
Durr
A.
Hahn-Barma
V.
Brice
A.
Pecheux
C.
Dode
C.
Feingold
J.
Homozygosity in Huntington's disease
J. Med. Genet.
 
1999
36
172
173
54
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
55
Gabizon
R.
Rosenmann
H.
Meiner
Z.
Kahana
I.
Kahana
E.
Shugart
Y.
Ott
J.
Prusiner
S.B.
Mutation and polymorphism of the prion protein gene in Libyan Jews with Creutzfeldt-Jakob disease (CJD)
Am. J. Hum. Genet.
 
1993
53
828
835
56
Lerer
I.
Merims
D.
Abeliovich
D.
Zlotogora
J.
Gadoth
N.
Machado-Joseph disease: correlation between the clinical features, the CAG repeat length and homozygosity for the mutation
Eur. J. Hum. Genet.
 
1996
4
3
7
57
Sobue
G.
Doyu
M.
Nakao
N.
Shimada
N.
Mitsuma
T.
Maruyama
H.
Kawakami
S.
Nakamura
S.
Homozygosity for Machado-Joseph disease gene enhances phenotypic severity
J. Neurol. Neurosurg. Psychiatry
 
1996
60
354
356
58
Sanpei
K.
Takano
H.
Igarashi
S.
Sato
T.
Oyake
M.
Sasaki
H.
Wakisaka
A.
Tashiro
K.
Ishida
Y.
Ikeuchi
T.
et al.  
Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT
Nat. Genet.
 
1996
14
277
284
59
Matsumura
R.
Futamura
N.
Fujimoto
Y.
Yanagimoto
S.
Horikawa
H.
Suzumura
A.
Takayanagi
T.
Spinocerebellar ataxia type 6. Molecular and clinical features of 35 Japanese patients including one homozygous for the CAG repeat expansion
Neurology
 
1997
49
1238
1243
60
Giraldo
M.
Lopera
F.
Siniard
A.L.
Corneveaux
J.J.
Schrauwen
I.
Carvajal
J.
Munoz
C.
Ramirez-Restrepo
M.
Gaiteri
C.
Myers
A.J.
et al.  
Variants in triggering receptor expressed on myeloid cells 2 are associated with both behavioral variant frontotemporal lobar degeneration and Alzheimer's disease
Neurobiol. Aging
 
2013
34
2077 e2011
2078
61
Reiner
A.P.
Beleza
S.
Franceschini
N.
Auer
P.L.
Robinson
J.G.
Kooperberg
C.
Peters
U.
Tang
H.
Genome-wide association and population genetic analysis of C-reactive protein in African American and Hispanic American women
Am. J. Hum. Genet.
 
2012
91
502
512
62
Cuyvers
E.
Bettens
K.
Philtjens
S.
Van Langenhove
T.
Gijselinck
I.
van der Zee
J.
Engelborghs
S.
Vandenbulcke
M.
Van Dongen
J.
Geerts
N.
et al.  
Investigating the role of rare heterozygous TREM2 variants in Alzheimer's disease and frontotemporal dementia
Neurobiol. Aging
 
2014
35
726 e711
729
63
Lattante
S.
Le Ber
I.
Camuzat
A.
Dayan
S.
Godard
C.
Van Bortel
I.
De Septenville
A.
Ciura
S.
Brice
A.
Kabashi
E.
TREM2 mutations are rare in a French cohort of patients with frontotemporal dementia
Neurobiol. Aging
 
2013
34
2443 e2441
2442
64
Rayaprolu
S.
Mullen
B.
Baker
M.
Lynch
T.
Finger
E.
Seeley
W.W.
Hatanpaa
K.J.
Lomen-Hoerth
C.
Kertesz
A.
Bigio
E.H.
et al.  
TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease
Mol. Neurodegener.
 
2013
8
19
65
Benitez
B.A.
Cruchaga
C.
TREM2 and neurodegenerative disease
N. Engl. J. Med.
 
2013
369
1567
1568
66
Nalls
M.A.
Duran
R.
Lopez
G.
Kurzawa-Akanbi
M.
McKeith
I.G.
Chinnery
P.F.
Morris
C.M.
Theuns
J.
Crosiers
D.
Cras
P.
et al.  
A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies
JAMA Neurol.
 
2013
70
727
735
67
Winder-Rhodes
S.E.
Evans
J.R.
Ban
M.
Mason
S.L.
Williams-Gray
C.H.
Foltynie
T.
Duran
R.
Mencacci
N.E.
Sawcer
S.J.
Barker
R.A.
Glucocerebrosidase mutations influence the natural history of Parkinson's disease in a community-based incident cohort
Brain
 
2013
136
392
399
68
Kitada
T.
Asakawa
S.
Hattori
N.
Matsumine
H.
Yamamura
Y.
Minoshima
S.
Yokochi
M.
Mizuno
Y.
Shimizu
N.
Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
Nature
 
1998
392
605
608
69
Veeriah
S.
Taylor
B.S.
Meng
S.
Fang
F.
Yilmaz
E.
Vivanco
I.
Janakiraman
M.
Schultz
N.
Hanrahan
A.J.
Pao
W.
et al.  
Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies
Nat. Genet.
 
2010
42
77
82
70
Plun-Favreau
H.
Lewis
P.A.
Hardy
J.
Martins
L.M.
Wood
N.W.
Cancer and neurodegeneration: between the devil and the deep blue sea
PLoS Genet.
 
2010
6
e1001257
71
Williams
F.M.
Bansal
A.T.
van Meurs
J.B.
Bell
J.T.
Meulenbelt
I.
Suri
P.
Rivadeneira
F.
Sambrook
P.N.
Hofman
A.
Bierma-Zeinstra
S.
et al.  
Novel genetic variants associated with lumbar disc degeneration in northern Europeans: a meta-analysis of 4600 subjects
Ann. Rheum. Dis
 
2012
72
Edwards
D.R.
Gilbert
J.R.
Hicks
J.E.
Myers
J.L.
Jiang
L.
Cummings
A.C.
Guo
S.
Gallins
P.J.
Konidari
I.
Caywood
L.
et al.  
Linkage and association of successful aging to the 6q25 region in large Amish kindreds
Age (Dordr)
 
2012
73
Low
S.K.
Kuchiba
A.
Zembutsu
H.
Saito
A.
Takahashi
A.
Kubo
M.
Daigo
Y.
Kamatani
N.
Chiku
S.
Totsuka
H.
et al.  
Genome-wide association study of pancreatic cancer in Japanese population
PLoS ONE
 
2010
5
e11824
74
Gieger
C.
Geistlinger
L.
Altmaier
E.
Hrabe de Angelis
M.
Kronenberg
F.
Meitinger
T.
Mewes
H.W.
Wichmann
H.E.
Weinberger
K.M.
Adamski
J.
et al.  
Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum
PLoS Genet.
 
2008
4
e1000282
75
Mitsui
J.
Takahashi
Y.
Goto
J.
Tomiyama
H.
Ishikawa
S.
Yoshino
H.
Minami
N.
Smith
D.I.
Lesage
S.
Aburatani
H.
et al.  
Mechanisms of genomic instabilities underlying two common fragile-site-associated loci, PARK2 and DMD, in germ cell and cancer cell lines
Am. J. Hum. Genet.
 
2010
87
75
89
76
Anderson
C.A.
Boucher
G.
Lees
C.W.
Franke
A.
D'Amato
M.
Taylor
K.D.
Lee
J.C.
Goyette
P.
Imielinski
M.
Latiano
A.
et al.  
Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47
Nat. Genet.
 
2011
43
246
252
77
Dubois
P.C.
Trynka
G.
Franke
L.
Hunt
K.A.
Romanos
J.
Curtotti
A.
Zhernakova
A.
Heap
G.A.
Adany
R.
Aromaa
A.
et al.  
Multiple common variants for celiac disease influencing immune gene expression
Nat. Genet.
 
2010
42
295
302
78
Barrett
J.H.
Iles
M.M.
Harland
M.
Taylor
J.C.
Aitken
J.F.
Andresen
P.A.
Akslen
L.A.
Armstrong
B.K.
Avril
M.F.
Azizi
E.
et al.  
Genome-wide association study identifies three new melanoma susceptibility loci
Nat. Genet.
 
2011
43
1108
1113
79
Nan
H.
Xu
M.
Zhang
J.
Zhang
M.
Kraft
P.
Qureshi
A.A.
Chen
C.
Guo
Q.
Hu
F.B.
Rimm
E.B.
et al.  
Genome-wide association study identifies nidogen 1 (NID1) as a susceptibility locus to cutaneous nevi and melanoma risk
Hum. Mol. Genet.
 
2011
20
2673
2679
80
Falchi
M.
Bataille
V.
Hayward
N.K.
Duffy
D.L.
Bishop
J.A.
Pastinen
T.
Cervino
A.
Zhao
Z.Z.
Deloukas
P.
Soranzo
N.
et al.  
Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi
Nat. Genet.
 
2009
41
915
919
81
Franke
A.
McGovern
D.P.
Barrett
J.C.
Wang
K.
Radford-Smith
G.L.
Ahmad
T.
Lees
C.W.
Balschun
T.
Lee
J.
Roberts
R.
et al.  
Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci
Nat. Genet.
 
2010
42
1118
1125
82
Barrett
J.C.
Hansoul
S.
Nicolae
D.L.
Cho
J.H.
Duerr
R.H.
Rioux
J.D.
Brant
S.R.
Silverberg
M.S.
Taylor
K.D.
Barmada
M.M.
et al.  
Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease
Nat. Genet.
 
2008
40
955
962
83
Jostins
L.
Ripke
S.
Weersma
R.K.
Duerr
R.H.
McGovern
D.P.
Hui
K.Y.
Lee
J.C.
Schumm
L.P.
Sharma
Y.
Anderson
C.A.
et al.  
Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease
Nature
 
2012
491
119
124
84
Zhang
F.R.
Huang
W.
Chen
S.M.
Sun
L.D.
Liu
H.
Li
Y.
Cui
Y.
Yan
X.X.
Yang
H.T.
Yang
R.D.
et al.  
Genomewide association study of leprosy
N. Engl. J. Med.
 
2009
361
2609
2618
85
Kirby
A.
Gnirke
A.
Jaffe
D.B.
Baresova
V.
Pochet
N.
Blumenstiel
B.
Ye
C.
Aird
D.
Stevens
C.
Robinson
J.T.
et al.  
Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing
Nat. Genet.
 
2013
45
299
303
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