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1.  Increased rate of sporadic and recurrent rare genic copy number variants in Parkinson's disease among Ashkenazi Jews 
To date, only one genome-wide study has assessed the contribution of copy number variants (CNVs) to Parkinson's disease (PD). We conducted a genome-wide scan for CNVs in a case–control dataset of Ashkenazi Jewish (AJ) origin (268 PD cases and 178 controls). Using high-confidence CNVs, we examined the global genome wide burden of large (≥100 kb) and rare (≤1% in the dataset) CNVs between cases and controls. A total of 986 such CNVs were observed in our dataset of 432 subjects. Overall global burden analyses did not reveal significant differences between cases and controls in CNV rate, distribution of deletions or duplications or number of genes affected by CNVs. Overall deletions (total CNV size and ≥2× frequency) were found 1.4 times more often in cases than in controls (P = 0.019). The large CNVs (≥500 kb) were also significantly associated with PD (P = 0.046, 1.24-fold higher in cases than in controls). Global burden was elevated for rare CNV regions. Specifically, for OVOS2 on Chr12p11.21, CNVs were observed only in PD cases (n = 7) but not in controls (P = 0.028) and this was experimentally validated. A total of 81 PD cases carried a rare genic CNV that was absent in controls. Ingenuity pathway analysis (IPA) identified ATXN3, FBXW7, CHCHD3, HSF1, KLC1, and MBD3 in the same disease pathway with known PD genes.
PMCID: PMC3782064  PMID: 24073418
Ashkenazi Jews; candidate genes; case–control study; CNV; Parkinson's disease
2.  Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies 
Human molecular genetics  2014;23(23):6139-6146.
Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson’s and Alzheimer’s diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
PMCID: PMC4222357  PMID: 24973356
3.  Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies 
Human Molecular Genetics  2014;23(23):6139-6146.
Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
PMCID: PMC4222357  PMID: 24973356
4.  Familial Aggregation of Cranial Tremor in Familial Essential Tremor 
Neuroepidemiology  2013;41(1):48-53.
Essential tremor (ET) is often familial and phenotypic features may be shared within families. Cranial (neck, voice, jaw) tremor is an important feature of ET. We examined whether cranial tremor aggregates in ET families, after controlling for other factors (age, tremor severity and duration).
Among ET probands and relatives enrolled in a genetic study at Columbia University (95 subjects in 28 families), we assessed the degree to which occurrence of cranial tremor in the proband predicted occurrence of cranial tremor in affected relatives.
Forty-five (47.4%) subjects had cranial tremor on neurological examination (probands 66.7%, relatives 39.7%). Among 28 families, 23 (82.1%) contained individuals with and individuals without cranial tremor, indicating a high degree of within-family heterogeneity. In comparison to subjects without cranial tremor, those with cranial tremor had higher total tremor scores (p<0.001), were older (p=0.003), and had tremor of longer duration (p=0.01). In logistic regression models, the odds of cranial tremor in a relative was not related to occurrence of cranial tremor in the proband (p>0.24).
Cranial tremor did not aggregate in families with ET; the major predictor of this disease feature was tremor severity rather than presence of cranial tremor in another family member.
PMCID: PMC3770156  PMID: 23712245
essential tremor; genetics; familial; clinical; cranial tremor; head tremor
5.  Prevalence and Features of Unreported Dystonia in a Family Study of “Pure” Essential Tremor 
Parkinsonism & related disorders  2012;19(3):359-362.
Essential tremor (ET) is considered to be a highly heritable disorder, yet no susceptibility genes have been identified. The search for ET genes is severely hampered by clinical and genetic heterogeneity; the existence of this heterogeneity complicates the genetic analyses. We sought to determine the prevalence and clinical features of unreported dystonia in a family study of “pure” ET.
ET probands and their reportedly affected first-and second-degree relatives were enrolled in a genetics study, the Family Study of Essential Tremor (FASET) at Columbia University Medical Center. The goal was to enroll cases with “pure” ET (i.e., ET without dystonia or other neurological problems). Each enrollee underwent a detailed neurological evaluation.
There were 100 enrollees (28 probands, 72 relatives). Dystonia (primarily torticollis) occurred in 9 (32.1%) of 28 families, with 5 cases in one family, 2 cases in two families, and 1 case in six families. Those affected with dystonia included 3 (10.7%) probands and 12 (16.7%) relatives. There was a gender predilection: 14/15 (93.3%) with dystonia vs. 41/85 (48.2%) without dystonia were women (p=0.001). Dystonia was previously undiagnosed in 14/15 (93.3%) cases.
Dystonia (esp. torticollis in women) was present in nearly one-third of the ET families in a genetics study, including 10.7% of ET probands. Dystonia was unreported and previously undiagnosed in nearly all of these individuals. The overarching biological issue is whether ET and dystonia should be regarded as one disease or two; this has obvious implications for the structuring of analyses in genetic studies.
PMCID: PMC3565033  PMID: 23089243
essential tremor; dystonia; genetics; familial; clinical
6.  Does Rate of Progression Run in Essential Tremor Families? Slower vs. Faster Progressors 
Parkinsonism & related disorders  2012;19(3):363-366.
Essential tremor (ET) is a progressive disorder, worsening gradually with time in most patients. Yet there are few data on the factors that influence rate of progression. ET is a highly familial disorder, and physicians often care for patients who have other affected family members. Do ET families differ from one another with respect to rate of progression? Are some families slower progressors and other families faster progressors? We are unaware of published data.
ET probands and relatives were enrolled in a cross-sectional genetic study at Columbia University. Rate of progression was calculated as total tremor score ÷ log disease duration.
There were 100 enrollees (28 probands, 72 relatives). Data from 78 enrollees (23 probands, 55 relatives) were selected for final analysis. The mean familial rate of progression ranged from as little as 8.4 to as much as 34.3, a >4-fold difference. In an analysis of variance, we found significant evidence of heterogeneity in the log rate of progression across families (p <0.001), with more than one-half (i.e., 55.4%) of the total variance in the log rate of progression explained by the family grouping.
Familial factors seem to affect rate of tremor progression in ET. There was a 4-fold difference across families in observed mean rate of progression; thus, some families seemed to be more rapid progressors than others. We hope these data may be used by clinicians to provide basic prognostic and family guidance information to their patients and families with ET.
PMCID: PMC3578031  PMID: 23121728
essential tremor; genetics; familial; clinical; rate of progression
7.  LINGO1 and LINGO2 variants are associated with essential tremor and Parkinson disease 
Neurogenetics  2010;11(4):401-408.
Genetic variation in the leucine-rich repeat and Ig domain containing 1 gene (LINGO1) was recently associated with an increased risk of developing essential tremor (ET) and Parkinson disease (PD). Herein, we performed a comprehensive study of LINGO1 and its paralog LINGO2 in ET and PD by sequencing both genes in patients (ET, n=95; PD, n=96) and by examining haplotype-tagging single-nucleotide polymorphisms (tSNPs) in a multicenter North American series of patients (ET, n=1,247; PD, n=633) and controls (n=642). The sequencing study identified six novel coding variants in LINGO1 (p.S4C, p.V107M, p.A277T, p.R423R, p.G537A, p.D610D) and three in LINGO2 (p.D135D, p.P217P, p.V565V), however segregation analysis did not support pathogenicity. The association study employed 16 tSNPs at the LINGO1 locus and 21 at the LINGO2 locus. One variant in LINGO1 (rs9652490) displayed evidence of an association with ET (odds ratio (OR)=0.63; P=0.026) and PD (OR=0.54; P=0.016). Additionally, four other tSNPs in LINGO1 and one in LINGO2 were associated with ET and one tSNP in LINGO2 associated with PD (P<0.05). Further analysis identified one tSNP in LINGO1 and two in LINGO2 which influenced age at onset of ET and two tSNPs in LINGO1 which altered age at onset of PD (P<0.05). Our results support a role for LINGO1 and LINGO2 in determining risk for and perhaps age at onset of ET and PD. Further studies are warranted to confirm these findings and to determine the pathogenic mechanisms involved.
PMCID: PMC3930084  PMID: 20369371
Essential tremor; Parkinson disease; LINGO1; LINGO2; Genetic association
8.  Clinical Classification of Borderline Cases in the Family Study of Essential Tremor: An Analysis of Phenotypic Features 
In genetic research on essential tremor (ET), certain individuals may be particularly challenging to categorize diagnostically.
In the Family Study of Essential Tremor (>200 enrollees), 28 participants with borderline clinical findings who did not meet strict criteria for ET were assigned final diagnoses of ET. We scrutinized the clinical features of these cases and the sensitivity/specificity of certain features that best separated them from 19 unaffected individuals.
Borderline ET cases differed from unaffected individuals in eight features: total tremor score, at least one kinetic tremor rating ≥1.5, at least one kinetic tremor rating ≥1.5 in the dominant arm, tremor rating during spiral drawing ≥1.5, higher spiral axis score, head tremor, complaint of tremor, and comment on tremor by others. The combination of at least one kinetic tremor rating ≥1.5 in the dominant arm and the presence of at least three of the remaining seven features predicted the clinician-assigned diagnosis in 88.6% of borderline ET vs. unaffected individuals (sensitivity 84.6%, specificity 94.4%).
In a family study, a small number of clinical features characterized borderline ET, and a particular combination of these separated the majority of these borderline cases from normals. These analyses may help researchers minimize diagnostic misclassification.
PMCID: PMC3925876  PMID: 24596662
Essential tremor; classification; genetic; clinical; epidemiology
9.  RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson’s disease risk 
Neuron  2013;77(3):425-439.
Recent genome-wide association studies have linked common variants in the human genome to Parkinson’s disease (PD) risk. Here we show that the consequences of variants at 2 such loci, PARK16 and LRRK2, are highly interrelated, both in terms of their broad impacts on human brain transcriptomes of unaffected carriers, and in terms of their associations with PD risk. Deficiency of the PARK16 locus gene RAB7L1 in primary rodent neurons, or of a RAB7L1 orthologue in Drosophila dopamine neurons, recapitulated degeneration observed with expression of a familial PD mutant form of LRRK2, whereas RAB7L1 overexpression rescued the LRRK2 mutant phenotypes. PD-associated defects in RAB7L1 or LRRK2 led to endolysosomal and Golgi apparatus sorting defects and deficiency of the VPS35 component of the retromer complex. Expression of wild-type VPS35, but not a familial PD-associated mutant form, rescued these defects. Taken together, these studies implicate retromer and lysosomal pathway alterations in PD risk.
PMCID: PMC3646583  PMID: 23395371
10.  Predicting Age of Onset in Familial Essential Tremor: How Much Does Age of Onset Run in Families? 
Neuroepidemiology  2013;40(4):269-273.
The extent to which age of onset of essential tremor (ET) aggregates in families is unknown; hence it is unclear whether information about age of onset in one family member can be used to predict the age of onset in others.
ET probands and relatives were enrolled in a genetic study at Columbia University.
Data from 26 probands and 52 relatives were analyzed. The probands’ age of onset correlated significantly with their relatives’ age of onset (r=0.50, p=0.001). In 57.7% of cases, the relative’s age of onset was within 10 years of the proband’s onset (i.e., a 20 year age range). The proportion of affected relatives with age at onset <20 years was 64.7% in the families of probands with onset younger than 20 years, but only 7.7% in the families of probands with onset ≥20 years, (p<0.001). There was little evidence for genetic anticipation; 9/18 (50.0%) children reported a younger age of onset than the proband.
In families containing multiple individuals with ET, age at onset of probands and relatives was significantly correlated. Age of onset may be most tightly linked in families in which the proband had a young age of onset.
PMCID: PMC3718305  PMID: 23363932
essential tremor; genetics; familial; clinical; age of onset
11.  Essential Tremor in a Charcot-Marie-Tooth Type 2C Kindred Does Not Segregate with the TRPV4 R269H Mutation 
Case Reports in Neurology  2014;6(1):1-6.
We investigated 4 members of a family with type 2C Charcot-Marie-Tooth (CMT) and self-reported essential tremor (ET). A heterozygous missense mutation, R269H, in the TRPV4 gene was previously reported in this family. Our genotypic data provided a rare opportunity to determine the etiology of the tremor.
Family study; the 4 tremor cases underwent a detailed neurological assessment.
The clinical diagnosis of ET was confirmed in all 4 tremor cases based on stringent published research criteria. Two of these also had CMT. We genotyped all 4 family members for the TRPV4 R269H mutation. We confirmed the presence of the TRPV4 R269H mutation in the 2 family members with ET and CMT; however, the TRPV4 R269H mutation did not segregate with ET in the same family.
In this particular CMT family, the tremor was clinically attributed to ET. Furthermore, genotype data indicated that the tremor was unlikely to be caused by incomplete penetrance or variable expressivity of the TRPV4 R269H mutation. Hence, the tremor likely represents ET. This establishes that in some CMT families the tremor diathesis likely represents a second disorder, namely ET.
PMCID: PMC3934698  PMID: 24575025
Essential tremor; Charcot-Marie-Tooth; Neuropathy; Genetics
12.  Lack of Association Between Cancer History and PARKIN Genotype: a Family Based Study in PARKIN/Parkinson’s Families 
Genes, chromosomes & cancer  2012;51(12):1109-1113.
A number of publications have attributed a tumor suppressive (TS) function to PARKIN, a gene associated with recessive familial early-onset Parkinson’s disease (EOPD). Discoveries of PARKIN deletions and point mutations in tumors, functional studies, and data from mouse models have been presented to support the hypothesis. We have asked whether PARKIN mutations are associated with history of cancer in humans. We interviewed 431 participants who were screened for PARKIN mutations, including 149 EOPD cases and their family members, who were unaware of mutation status. We found no significant difference in self-reported history of cancer among carriers of one or two PARKIN mutations and non-carriers, odds ratio 0.75 (95% confidence interval 0.27-1.83). In particular, no increase in cancer history was seen among homozygous and compound heterozygous mutation carriers compared to non-carriers. Therefore, we hypothesize that published studies attributing TS capability to PARKIN merit further exploration and we present a reevaluation of these data with respect to patterns of mutation frequencies in normal and cancer cells. We conclude that although Parkin may exert a suppressive effect in mice, further studies are required prior to assigning a TS function to PARKIN in humans.
PMCID: PMC3465486  PMID: 22927236
Tumor suppressor; PARKIN - Early-onset Parkinson’s cohort; cancer risk
13.  The MAPT H1 haplotype is associated with tangle-predominant dementia 
Acta neuropathologica  2012;124(5):693-704.
Tangle-predominant dementia (TPD) patients exhibit cognitive decline that is clinically similar to early to moderate-stage Alzheimer disease (AD), yet autopsy reveals neurofibrillary tangles in the medial temporal lobe composed of the microtubule-associated protein tau without significant amyloid-beta (Aβ)-positive plaques. We performed a series of neuropathological, biochemical and genetic studies using autopsy brain tissue drawn from a cohort of 34 TPD, 50 AD and 56 control subjects to identify molecular and genetic signatures of this entity. Biochemical analysis demonstrates a similar tau protein isoform composition in TPD and AD, which is compatible with previous histological and ultrastructural studies. Further, biochemical analysis fails to uncover elevation of soluble Aβ in TPD frontal cortex and hippocampus compared to control subjects, demonstrating that non-plaque-associated Aβ is not a contributing factor. Unexpectedly, we also observed high levels of secretory amyloid precursor protein α (sAPPα) in the frontal cortex of some TPD patients compared to AD and control subjects, suggesting differences in APP processing. Finally, we tested whether TPD is associated with changes in the tau gene (MAPT). Haplotype analysis demonstrates a strong association between TPD and the MAPT H1 haplotype, a genomic inversion associated with some tauopathies and Parkinson disease (PD), when compared to age-matched control subjects with mild degenerative changes, i.e., successful cerebral aging. Next-generation resequencing of MAPT followed by association analysis shows an association between TPD and two polymorphisms in the MAPT 3′ untranslated region (UTR). These results support the hypothesis that haplotype-specific variation in the MAPT 3′ UTR underlies an Aβ-independent mechanism for neurodegeneration in TPD.
PMCID: PMC3608475  PMID: 22802095
Dementia; Neurofibrillary tangle; Tau; Amyloid; MAPT; 3′ Untranslated region; Aging; Alzheimer’s disease; sAPPα
14.  Genetic variants of α-synuclein are not associated with essential tremor 
Given the overlap between Parkinson disease and essential tremor, we examined genetic variants in α-synuclein (SNCA) as risk determinants for essential tremor.
Samples from 661 essential tremor subjects and 1,316 control subjects from four participating North American sites were included in this study. Parkinson disease samples (n=427) were compared against controls for two cohorts. Twenty variants were selected for association analysis within the SNCA locus. Individual logistic regression analyses against essential tremor diagnosis and then combined using meta-analysis was run for each variant.
Our results do not show a significant association between variants in the SNCA locus and risk of essential tremor, while the established association of SNCA variants with Parkinson disease risk was observed.
While genetic factors are likely to play a large role in essential tremor pathogenesis our results do not support a role for common SNCA genetic variants in risk for essential tremor.
PMCID: PMC3677575  PMID: 22025277
tremor; essential tremor; association studies in genetics; Parkinson’s disease; parkinsonism; synuclein
15.  Clinical and pathological characteristics of LRRK2 G2019S patients with PD 
Journal of Molecular Neuroscience  2011;47(1):139-143.
To describe the neuropathologic findings in three LRRK2 G2019S carriers with Parkinson’s disease (PD).
We cross referenced a list of 956 PD individuals that had been previously genotyped in clinical studies at Columbia University, with 282 subjects with a parkinsonian syndrome who came to autopsy in our brain bank since 1991. We found three autopsies of G2019S mutation carriers. Pathological analyses of the samples were blind to the genetic findings. We retrospectively reviewed the clinical records of the three patients.
All three had a clinical and pathological diagnosis of PD. Cognitive impairment was a late feature in two out of three patients. Cortical involvement varied significantly: one had diffuse Lewy Body (LB) pathology, tau inclusions and amyloid pathology consistent with advanced Alzheimer’s disease; one had diffuse cortical LB and one had only brainstem predominant LB pathology.
Cognitive impairment may be a long term complication in G2019S mutation carriers. However, the extent of cortical involvement is variable. Larger longitudinal follow up of LRRK2 G2019S mutation carriers is required to assess for risk factors for cortical involvement and dementia.
PMCID: PMC3335886  PMID: 22194196
Parkinson’s disease; Lewy Bodies; LRRK2 gene mutation; Dementia
16.  Meta-analysis of Parkinson disease: Identification of a novel locus, RIT2 
Annals of Neurology  2012;71(3):370-384.
Genome-wide association (GWAS) methods have identified genes contributing to Parkinson disease (PD); we sought to identify additional genes associated with PD susceptibility.
A two stage design was used. First, individual level genotypic data from five recent PD GWAS (Discovery Sample: 4,238 PD cases and 4,239 controls) were combined. Following imputation, a logistic regression model was employed in each dataset to test for association with PD susceptibility and results from each dataset were meta-analyzed. Second, 768 SNPs were genotyped in an independent Replication Sample (3,738 cases and 2,111 controls).
Genome-wide significance was reached for SNPs in SNCA (rs356165, G: odds ratio (OR)=1.37; p=9.3 × 10−21), MAPT (rs242559, C: OR=0.78; p=1.5 × 10−10), GAK/DGKQ (rs11248051, T:OR=1.35; p=8.2 × 10−9/ rs11248060, T: OR=1.35; p=2.0×10−9), and the HLA region (rs3129882, A: OR=0.83; p=1.2 × 10−8), which were previously reported. The Replication Sample confirmed the associations with SNCA, MAPT, and the HLA region and also with GBA (E326K OR=1.71; p=5 × 10−8 Combined Sample) (N370 OR=3.08; p=7 × 10−5 Replication sample). A novel PD susceptibility locus, RIT2, on chromosome 18 (rs12456492; p=5 × 10−5 Discovery Sample; p=1.52 × 10−7 Replication sample; p=2 × 10−10 Combined Sample) was replicated. Conditional analyses within each of the replicated regions identified distinct SNP associations within GBA and SNCA, suggesting that there may be multiple risk alleles within these genes.
We identified a novel PD susceptibility locus, RIT2, replicated several previously identified loci, and identified more than one risk allele within SNCA and GBA.
PMCID: PMC3354734  PMID: 22451204
17.  Candidate Sequence Variants and Fetal Hemoglobin in Children with Sickle Cell Disease Treated with Hydroxyurea 
PLoS ONE  2013;8(2):e55709.
Fetal hemoglobin level is a heritable complex trait that strongly correlates swith the clinical severity of sickle cell disease. Only few genetic loci have been identified as robustly associated with fetal hemoglobin in patients with sickle cell disease, primarily adults. The sole approved pharmacologic therapy for this disease is hydroxyurea, with effects largely attributable to induction of fetal hemoglobin.
Methodology/Principal Findings
In a multi-site observational analysis of children with sickle cell disease, candidate single nucleotide polymorphisms associated with baseline fetal hemoglobin levels in adult sickle cell disease were examined in children at baseline and induced by hydroxyurea therapy. For baseline levels, single marker analysis demonstrated significant association with BCL11A and the beta and epsilon globin loci (HBB and HBE, respectively), with an additive attributable variance from these loci of 23%. Among a subset of children on hydroxyurea, baseline fetal hemoglobin levels explained 33% of the variance in induced levels. The variant in HBE accounted for an additional 13% of the variance in induced levels, while variants in the HBB and BCL11A loci did not contribute beyond baseline levels.
These findings clarify the overlap between baseline and hydroxyurea-induced fetal hemoglobin levels in pediatric disease. Studies assessing influences of specific sequence variants in these and other genetic loci in larger populations and in unusual hydroxyurea responders are needed to further understand the maintenance and therapeutic induction of fetal hemoglobin in pediatric sickle cell disease.
PMCID: PMC3567082  PMID: 23409025
18.  Creation of an Open-Access, Mutation-Defined Fibroblast Resource for Neurological Disease Research 
PLoS ONE  2012;7(8):e43099.
Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.
PMCID: PMC3428297  PMID: 22952635
19.  Neuropsychological profile of parkin mutation carriers with and without Parkinson disease: the CORE-PD study 
The cognitive profile of early onset Parkinson’s disease (EOPD) has not been clearly defined. Mutations in the parkin gene are the most common genetic risk factor for EOPD and may offer information about the neuropsychological pattern of performance in both symptomatic and asymptomatic mutation carriers.
EOPD probands and their first-degree relatives who did not have Parkinson’s disease (PD) were genotyped for mutations in the parkin gene and administered a comprehensive neuropsychological battery. Performance was compared between EOPD probands with (N=43) and without (N=52) parkin mutations. The same neuropsychological battery was administered to 217 first-degree relatives to assess neuropsychological function in individuals who carry parkin mutations but do not have PD.
No significant differences in neuropsychological test performance were found between parkin carrier and non-carrier probands. Performance also did not differ between EOPD non-carriers and carrier subgroups (i.e. heterozygotes, compound heterozygotes/homozygotes). Similarly, no differences were found among unaffected family members across genotypes. Mean neuropsychological test performance was within normal range in all probands and relatives.
Carriers of parkin mutations, whether or not they have PD, do not perform differently on neuropsychological measures as compared to non-carriers. The cognitive functioning of parkin carriers over time warrants further study.
PMCID: PMC3366462  PMID: 21092386
Parkinson’s disease; genetics; neuropsychological assessment; genotype; PARK2; parkin mutation
20.  A Genome-Wide Scan of Ashkenazi Jewish Crohn's Disease Suggests Novel Susceptibility Loci 
PLoS Genetics  2012;8(3):e1002559.
Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD–susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2–4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10−6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10−8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10−9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10−8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10−8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10−9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.
Author Summary
Crohn's disease causes inflammation of the digestive tract resulting from the interaction of normal gut bacteria with the host immune system in genetically predisposed individuals. People of Jewish heritage have an increased risk of developing Crohn's disease compared to non-Jewish Europeans. So far, 71 genetic variants that increase the risk of Crohn's disease have been identified in individuals of European ancestry. Here, we take advantage of recent technical and methodological advances to explore Crohn's diseases-related genetic variants specific to the Ashkenazi Jewish population. We examined 6,347 individuals whose Jewish ancestry was confirmed by a large number of genetic markers and detected several variants associated with the increased risk of Crohn' disease. We confirmed the involvement of 12 known Crohn's disease risk variants in Ashkenazi Jews and identified novel genetic regions not previously found in non-Jewish European populations. Further studies of these regions may help discover biological pathways affecting susceptibility to Crohn's disease and lead to the development of novel treatments. This study also demonstrates the complementary value of genetic studies in isolated populations, like the Ashkenazim.
PMCID: PMC3297573  PMID: 22412388
21.  SORCS1 Alters Amyloid Precursor Protein Processing and Variants May Increase Alzheimer’s Disease Risk 
Annals of neurology  2011;69(1):47-64.
Sorting mechanisms that cause the amyloid precursor protein (APP) and the β-secretases and γ-secretases to colocalize in the same compartment play an important role in the regulation of Aβ production in Alzheimer’s disease (AD). We and others have reported that genetic variants in the Sortilin-related receptor (SORL1) increased the risk of AD, that SORL1 is involved in trafficking of APP, and that under expression of SORL1 leads to overproduction of Aβ. Here we explored the role of one of its homologs, the sortilin-related VPS10 domain containing receptor 1 (SORCS1), in AD.
We analyzed the genetic associations between AD and 16 SORCS1–single nucleotide polymorphisms (SNPs) in 6 independent data sets (2,809 cases and 3,482 controls). In addition, we compared SorCS1 expression levels of affected and unaffected brain regions in AD and control brains in microarray gene expression and real-time polymerase chain reaction (RT-PCR) sets, explored the effects of significant SORCS1-SNPs on SorCS1 brain expression levels, and explored the effect of suppression and overexpression of the common SorCS1 isoforms on APP processing and Aβ generation.
Inherited variants in SORCS1 were associated with AD in all datasets (0.001 < p < 0.049). In addition, SorCS1 influenced APP processing. While overexpression of SorCS1 reduced γ-secretase activity and Aβ levels, the suppression of SorCS1 increased γ-secretase processing of APP and the levels of Aβ.
These data suggest that inherited or acquired changes in SORCS1 expression or function may play a role in the pathogenesis of AD.
PMCID: PMC3086759  PMID: 21280075
22.  Genome-Wide association study identifies candidate genes for Parkinson's disease in an Ashkenazi Jewish population 
BMC Medical Genetics  2011;12:104.
To date, nine Parkinson disease (PD) genome-wide association studies in North American, European and Asian populations have been published. The majority of studies have confirmed the association of the previously identified genetic risk factors, SNCA and MAPT, and two studies have identified three new PD susceptibility loci/genes (PARK16, BST1 and HLA-DRB5). In a recent meta-analysis of datasets from five of the published PD GWAS an additional 6 novel candidate genes (SYT11, ACMSD, STK39, MCCC1/LAMP3, GAK and CCDC62/HIP1R) were identified. Collectively the associations identified in these GWAS account for only a small proportion of the estimated total heritability of PD suggesting that an 'unknown' component of the genetic architecture of PD remains to be identified.
We applied a GWAS approach to a relatively homogeneous Ashkenazi Jewish (AJ) population from New York to search for both 'rare' and 'common' genetic variants that confer risk of PD by examining any SNPs with allele frequencies exceeding 2%. We have focused on a genetic isolate, the AJ population, as a discovery dataset since this cohort has a higher sharing of genetic background and historically experienced a significant bottleneck. We also conducted a replication study using two publicly available datasets from dbGaP. The joint analysis dataset had a combined sample size of 2,050 cases and 1,836 controls.
We identified the top 57 SNPs showing the strongest evidence of association in the AJ dataset (p < 9.9 × 10-5). Six SNPs located within gene regions had positive signals in at least one other independent dbGaP dataset: LOC100505836 (Chr3p24), LOC153328/SLC25A48 (Chr5q31.1), UNC13B (9p13.3), SLCO3A1(15q26.1), WNT3(17q21.3) and NSF (17q21.3). We also replicated published associations for the gene regions SNCA (Chr4q21; rs3775442, p = 0.037), PARK16 (Chr1q32.1; rs823114 (NUCKS1), p = 6.12 × 10-4), BST1 (Chr4p15; rs12502586, p = 0.027), STK39 (Chr2q24.3; rs3754775, p = 0.005), and LAMP3 (Chr3; rs12493050, p = 0.005) in addition to the two most common PD susceptibility genes in the AJ population LRRK2 (Chr12q12; rs34637584, p = 1.56 × 10-4) and GBA (Chr1q21; rs2990245, p = 0.015).
We have demonstrated the utility of the AJ dataset in PD candidate gene and SNP discovery both by replication in dbGaP datasets with a larger sample size and by replicating association of previously identified PD susceptibility genes. Our GWAS study has identified candidate gene regions for PD that are implicated in neuronal signalling and the dopamine pathway.
PMCID: PMC3166909  PMID: 21812969
Parkinson's disease; GWAS; Ashkenazi Jews; case-control study; candidate genes
23.  Replication of the LINGO1 gene association with essential tremor in a North American population 
A marker in the LINGO1 gene, rs9652490, showing significant genome-wide association with essential tremor (ET), was recently reported in an Icelandic population. To replicate this association in an independent population from North America, we genotyped 15 SNPs in the LINGO1 gene in 257 Caucasian ET cases (‘definite,' ‘probable' or ‘possible') and 265 controls enrolled in an epidemiological study at Columbia University. We observed a marginally significant association with allele G of the marker rs9652490 (P=0.0569, odds ratio (OR)=1.33). However, for ‘definite' or ‘probable' ET, rs9652490 was significantly associated with ET (P=0.03, OR=1.41). Our subsequent analysis of early-onset ET (age at onset <40 years) revealed that three SNPs, rs177008, rs13313467 and rs8028808, were significantly associated with ET (P=0.028, OR=1.52; P=0.0238, OR=1.54; and P=0.0391, OR=1.55, respectively). These three SNPs represent a 2.3 kb haplotype. Finally, a meta-analysis of three published studies confirms allelic association with rs9652490 and two adjacent SNPs. Our study independently confirms that the LINGO1 gene is a risk factor for ET in a Caucasian population in North America, and further shows that those with early-onset ET are likely to be at high risk.
PMCID: PMC2987362  PMID: 20372186
essential tremor; LINGO1; association; risk factor
24.  Mutations in the Parkinson’s disease genes, Leucine Rich Repeat Kinase 2 (LRRK2) and Glucocerebrosidase (GBA), are not associated with essential tremor 
Parkinsonism & related disorders  2009;16(2):132-135.
We evaluated an association between essential tremor (ET) and the Parkinson’s disease (PD) genes, Leucine Rich Repeat Kinase 2 (LRRK2) and Glucocerebrosidase (GBA). Clinical studies demonstrate an association between ET and PD, suggesting possible shared pathophysiologies, yet LRRK2 has rarely been studied in ET, and GBA, not at all. ET cases (n = 275, including 42 with rest tremor) and controls (n = 289) were enrolled in an epidemiological study (Columbia University). Post-mortem brain tissue samples were obtained on 24 additional ET cases, including 3 with brainstem Lewy bodies. We performed a comprehensive analysis of the LRRK2 gene by genotyping 4 LRRK2 mutations (G2019S, I2020T, R1441C and Y1699C), 2 rare LRRK2 variants (L1114L and I1122V) and 19 LRRK2 SNPs. All GBA exons were sequenced in a subset of 93 Ashkenazi Jewish (AJ) cases, 62 AJ controls and 24 ET brains. LRRK2 mutations were not found in any ET cases or ET brains and none of the LRRK2 SNPs was associated with ET. GBA mutations were found in 7.5% (7/93) of AJ ET cases and 4.8% (3/62) of AJ controls (p = 0.75). 8.3% (2/24) of ET brains carried a GBA mutation. Four different heterozygous mutations were identified, including 3 previously reported mutations (N370S, R496H, and E326K) and 1 new missense variant (R44C). As suggested by several smaller prior reports, the known mutations for the LRRK2 gene are not risk factors for ET. Furthermore, a similar frequency of GBA mutations in AJ ET cases and controls suggests that GBA is not a common cause of ET either.
PMCID: PMC2822079  PMID: 19527940
Essential tremor; LRRK2; GBA mutation; Association; Risk factor
25.  Multi-center analysis of glucocerebrosidase mutations in Parkinson disease 
The New England journal of medicine  2009;361(17):1651-1661.
Recent studies indicate an increased frequency of mutations in the gene for Gaucher disease, glucocerebrosidase (GBA), among patients with Parkinson disease. An international collaborative study was conducted to ascertain the frequency of GBA mutations in ethnically diverse patients with Parkinson disease.
Sixteen centers participated, including five from the Americas, six from Europe, two from Israel and three from Asia. Each received a standard DNA panel to compare genotyping results. Genotypes and phenotypic data from patients and controls were analyzed using multivariate logistic regression models and the Mantel Haenszel procedure to estimate odds ratios (ORs) across studies. The sample included 5691 patients (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews).
All 16 centers could detect GBA mutations, L444P and N370S, and the two were found in 15.3% of Ashkenazi patients with Parkinson disease (ORs = 4.95 for L444P and 5.62 for N370S), and in 3.2% of non-Ashkenazi patients (ORs = 9.68 for L444P and 3.30 for N370S). GBA was sequenced in 1642 non-Ashkenazi subjects, yielding a frequency of 6.9% for all mutations, demonstrate that limited mutation screens miss half the mutant alleles. The presence of any GBA mutation was associated with an OR of 5.43 across studies. Clinically, although phenotypes varied, subjects with a GBA mutation presented earlier, and were more likely to have affected relatives and atypical manifestations.
Data collected from sixteen centers demonstrate that there is a strong association between GBA mutations and Parkinson disease.
PMCID: PMC2856322  PMID: 19846850

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