Haydeh Payami

Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

We conducted a meta-analysis of Parkinsons disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinsons disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55–4.30; P = 2 × 10−16). We also show six risk loci associated with proximal gene expression or DNA methylation.

Identification of a Novel LRRK2 Mutation Linked to Autosomal Dominant Parkinsonism: Evidence of a Common Founder across European Populations

Autosomal dominant parkinsonism has been attributed to pathogenic amino acid substitutions in leucine-rich repeat kinase 2 (LRRK2). By sequencing multiplex families consistent with a PARK8 assignment, we identified a novel heterozygous LRRK2 mutation. A referral sample of 248 affected probands from families with autosomal dominant parkinsonism was subsequently assessed; 7 (2.8%) were found to carry a heterozygous LRRK2 6055G-->A transition (G2019S). These seven patients originate from the United States, Norway, Ireland, and Poland. In samples of patients with idiopathic Parkinson disease (PD) from the same populations, further screening identified six more patients with LRRK2 G2019S; no mutations were found in matched control individuals. Subsequently, 42 family members of the 13 probands were examined; 22 have an LRRK2 G2019S substitution, 7 with a diagnosis of PD. Of note, all patients share an ancestral haplotype indicative of a common founder, and, within families, LRRK2 G2019S segregates with disease (multipoint LOD score 2.41). Penetrance is age dependent, increasing from 17% at age 50 years to 85% at age 70 years. In summary, our study demonstrates that LRRK2 G2019S accounts for parkinsonism in several families within Europe and North America. Our work highlights the fact that a proportion of clinically typical, late-onset PD cases have a genetic basis.

Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease

Parkinsons disease is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study of 2,000 individuals with Parkinsons disease (cases) and 1,986 unaffected controls from the NeuroGenetics Research Consortium (NGRC). We confirmed associations with SNCA and MAPT, replicated an association with GAK (using data from the NGRC and a previous study, P = 3.2 × 10−9) and detected a new association with the HLA region (using data from the NGRC only, P = 2.9 × 10−8), which replicated in two datasets (meta-analysis P = 1.9 × 10−10). The HLA association was uniform across all genetic and environmental risk strata and was strong in sporadic (P = 5.5 × 10−10) and late-onset (P = 2.4 × 10−8) disease. The association peak we found was at rs3129882, a noncoding variant in HLA-DRA. Two studies have previously suggested that rs3129882 influences expression of HLA-DR and HLA-DQ. The brains of individuals with Parkinsons disease show upregulation of DR antigens and the presence of DR-positive reactive microglia, and nonsteroidal anti-inflammatory drugs reduce Parkinsons disease risk. The genetic association with HLA supports the involvement of the immune system in Parkinsons disease and offers new targets for drug development.

Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics : The PDGene database

More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinsons disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of ∼27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P<5×10−8) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P = 1.3×10−8). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies.

The Number of Trait Loci in Late-Onset Alzheimer Disease

Although it is clear that apoE plays an important role in the genetics of late-onset Alzheimer disease (AD), evidence exists that additional genes may play a role in AD, and estimates of the total contribution of apoE to the variance in onset of AD vary widely. Unfortunately, little information is available on the number and contribution of additional genes. We estimated the number of additional quantitative-trait loci and their contribution to the variance in age at onset of AD, as well as the contribution of apoE and sex, in an oligogenic segregation analysis of 75 families (742 individuals) ascertained for members with late-onset AD. We found evidence that four additional loci make a contribution to the variance in age at onset of late-onset AD that is similar to or greater in magnitude than that made by apoE, with one locus making a contribution several times greater than that of apoE. Additionally, we confirmed previous findings of a dose effect for the apoE varepsilon4 allele, a protective effect for the varepsilon2 allele, evidence for allelic interactions at the apoE locus, and a small protective effect for males. Furthermore, although we estimate that the apoE genotype can make a difference of </=17 years in age at onset of AD, our estimate of the contribution of apoE (7%-9%) to total variation in onset of AD is somewhat smaller than that which has previously been reported. Our results suggest that several genes that have not yet been localized may play a larger role than does apoE in late-onset AD.

Cognitive Markers Preceding Alzheimer's Dementia in the Healthy Oldest Old

OBJECTIVE: To look for preclinical markers of Alzheimers dementia in a sample of healthy, oldest old individuals.

Meta‐analysis of Parkinson's Disease: Identification of a novel locus, RIT2

Genome‐wide association (GWAS) methods have identified genes contributing to Parkinsons disease (PD); we sought to identify additional genes associated with PD susceptibility.

Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson's Disease Modifier Gene via Interaction with Coffee

Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinsons disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNPs main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P2df = 10−6, GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10−7) but not in light coffee-drinkers. The a priori Replication hypothesis that “Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers” was confirmed: ORReplication = 0.59, PReplication = 10−3; ORPooled = 0.51, PPooled = 7×10−8. Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10−3), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10−13). Imputation revealed a block of SNPs that achieved P2df<5×10−8 in GWAIS, and OR = 0.41, P = 3×10−8 in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients.

Cognitive performance of GBA mutation carriers with early-onset PD The CORE-PD study

Objective: To assess the cognitive phenotype of glucocerebrosidase (GBA) mutation carriers with early-onset Parkinson disease (PD). Methods: We administered a neuropsychological battery and the University of Pennsylvania Smell Identification Test (UPSIT) to participants in the CORE-PD study who were tested for mutations in PARKIN, LRRK2, and GBA. Participants included 33 GBA mutation carriers and 60 noncarriers of any genetic mutation. Primary analyses were performed on 26 GBA heterozygous mutation carriers without additional mutations and 39 age- and PD duration–matched noncarriers. Five cognitive domains, psychomotor speed, attention, memory, visuospatial function, and executive function, were created from transformed z scores of individual neuropsychological tests. Clinical diagnoses (normal, mild cognitive impairment [MCI], dementia) were assigned blind to genotype based on neuropsychological performance and functional impairment as assessed by the Clinical Dementia Rating (CDR) score. The association between GBA mutation status and neuropsychological performance, CDR, and clinical diagnoses was assessed. Results: Demographics, UPSIT, and Unified Parkinsons Disease Rating Scale–III performance did not differ between GBA carriers and noncarriers. GBA mutation carriers performed more poorly than noncarriers on the Mini-Mental State Examination (p = 0.035), and on the memory (p = 0.017) and visuospatial (p = 0.028) domains. The most prominent differences were observed in nonverbal memory performance (p < 0.001). Carriers were more likely to receive scores of 0.5 or higher on the CDR (p < 0.001), and a clinical diagnosis of either MCI or dementia (p = 0.004). Conclusion: GBA mutation status may be an independent risk factor for cognitive impairment in patients with PD.

Combined Effects of Smoking, Coffee, and NSAIDs on Parkinson's Disease Risk

Inverse associations of Parkinsons disease (PD) with cigarette smoking, coffee drinking, and nonsteroidal anti‐inflammatory drug (NSAID) use have been reported individually, but their joint effects have not been examined. To quantify associations with PD for the individual, two‐way and three‐way combinations of these factors, a case–control association study with 1,186 PD patients and 928 controls was conducted. The study setting was the NeuroGenetics Research Consortium. Subjects completed a structured questionnaire regarding smoking, coffee, and NSAID consumption. Odds ratios were calculated using unconditional logistic regression. Smoking, coffee, and over the counter NSAID use as individual factors exhibited significantly reduced risks of 20% to 30%. The two‐way and three‐way combinations were associated with risk reduction of 37% to 49%, and 62%, respectively. Smoking and coffee exhibited significant inverse risk trends with increasing cumulative exposures, suggesting dose–response relations. With respect to the combination of all three exposures, persons who were at the highest exposure strata for smoking and coffee and used NSAIDs had an estimated 87% reduction in risk (OR = 0.13, 95% CI = 0.06–0.29). Whether this finding reflects true biologic protection needs to be investigated.