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1.  A genetic basis for the variable effect of smoking/nicotine on Parkinson's disease 
The pharmacogenomics journal  2012;13(6):10.1038/tpj.2012.38.
Prior studies have established an inverse association between cigarette-smoking and the risk of developing Parkinson's disease (PD), and currently, disease-modifying potential of the nicotine-patch is being tested in clinical trials. To identify genes that interact with the effect of smoking/nicotine, we conducted genome-wide interaction studies in humans and in Drosophila. We identified SV2C which encodes a synaptic-vesicle protein in PD-vulnerable substantia-nigra (P=1×10-7 for gene-smoking interaction on PD risk), and CG14691 which is predicted to encode a synaptic-vesicle protein in Drosophila (P=2×10-11 for nicotine-paraquat interaction on gene-expression). SV2C is biologically plausible because nicotine enhances release of dopamine through synaptic vesicles, and PD is caused by depletion of dopamine. Effect of smoking on PD varied by SV2C genotype from protective to neutral to harmful (P=5×10-10). Taken together, cross-validating evidence from humans and Drosophila suggest SV2C is involved in PD pathogenesis and it might be a useful marker for pharmacogenomics studies involving nicotine.
doi:10.1038/tpj.2012.38
PMCID: PMC3538110  PMID: 23032990
SV2C; Nicotine; Parkinson's Disease
2.  Anorectal atresia and variants at predicted regulatory sites in candidate genes 
Annals of human genetics  2012;77(1):31-46.
SUMMARY
Anorectal atresia is a serious birth defect of largely unknown etiology but candidate genes have been identified in animal studies and human syndromes. Because alterations in the activity of these genes might lead to anorectal atresia, we selected 71 common variants predicted to be in transcription factor binding sites, CpG windows, splice sites, and miRNA target sites of 25 candidate genes, and tested for their association with anorectal atresia. The study population comprised 150 anorectal atresia cases and 623 control infants without major malformations. Variants predicted to affect transcription factor binding, splicing, and DNA methylation in WNT3A, PCSK5, TCF4, MKKS, GLI2, HOXD12, and BMP4 were associated with anorectal atresia based on a nominal P value <0.05. The GLI2 and BMP4 variants are reported to be moderately associated with gene expression changes (Spearman’s rank correlation coefficients between −0.260 and 0.226). We did not find evidence for interaction between maternal pre-pregnancy obesity and variants in MKKS, a gene previously associated with obesity, on the risk of anorectal atresia. Our results for MKKS support previously suggested associations with anorectal malformations. Our findings suggest that more research is needed to determine whether altered GLI2 and BMP4 expression is important in anorectal atresia in humans.
doi:10.1111/j.1469-1809.2012.00734.x
PMCID: PMC3535506  PMID: 23127126
anorectal malformations; imperforate anus; hindgut; congenital abnormalities
3.  Evaluation of Genes Involved in Limb Development, Angiogenesis, and Coagulation as Risk Factors for Congenital Limb Deficiencies 
We conducted a population-based case-control study of single nucleotide polymorphisms (SNPs) in selected genes to find common variants that play a role in the etiology of limb deficiencies (LD)s. Included in the study were 389 infants with LDs of unknown cause and 980 unaffected controls selected from all births in New York State (NYS) for the years 1998 to 2005. We used cases identified from the NYS Department of Health (DOH) Congenital Malformations Registry. Genotypes were obtained for 132 SNPs in genes involved in limb development (SHH, WNT7A, FGF4, FGF8, FGF10, TBX3, TBX5, SALL4, GREM1, GDF5, CTNNB1, EN1, CYP26A1, CYP26B1), angiogenesis (VEGFA, HIF1A, NOS3), and coagulation (F2, F5, MTHFR). Genotype call rates were >97% and SNPs were tested for departure from Hardy-Weinberg expectations by race/ethnic subgroups. For each SNP, odds ratios (OR)s and confidence intervals (CI)s were estimated and corrected for multiple comparisons for all LDs combined and for LD subtypes. Among non-Hispanic white infants, associations between FGF10 SNPs rs10805683 and rs13170645 and all LDs combined were statistically significant following correction for multiple testing (OR=1.99; 95% CI=1.43-2.77; uncorrected p=0.000043 for rs10805683 heterozygous genotype, and OR=2.37; 95% CI=1.48-3.78; uncorrected p=0.00032 for rs13170645 homozygous minor genotype). We also observed suggestive evidence for associations with SNPs in other genes including CYP26B1 and WNT7A. Animal studies have shown that FGF10 induces formation of the apical ectodermal ridge and is necessary for limb development. Our data suggest that common variants in FGF10 increase the risk for a wide range of non-syndromic limb deficiencies.
doi:10.1002/ajmg.a.35565
PMCID: PMC3448837  PMID: 22965740
limb deficiencies; polymorphisms; FGF10
4.  A genome-wide association study identifies susceptibility loci for non-syndromic sagittal craniosynostosis near BMP2 and within BBS9 
Nature genetics  2012;44(12):1360-1364.
Sagittal craniosynostosis is the most common form of craniosynostosis, affecting approximately one of 5,000 newborns. We conducted the first genome-wide association study (GWAS) for non-syndromic sagittal craniosynostosis (sNSC) using 130 non-Hispanic white (NHW) case-parent trios. Robust associations were observed in a 120 kb region downstream of BMP2, flanked by rs1884302 (P = 1.13 × 10−14; odds ratio [OR] = 4.58) and rs6140226 (P = 3.40 × 10−11; OR = 0.24) and within a 167 kb region of BBS9 between rs10262453 (P = 1.61 × 10−10; OR=0.19) and rs17724206 (P = 1.50 × 10−8; OR = 0.22). We replicated the associations to both loci [rs1884302 (P = 4.39 × 10−31); rs10262453 (P = 3.50 × 10−14)] in an independent NHW population of 172 unrelated sNSC probands and 548 controls. Both BMP2 and BBS9 are genes with a role in skeletal development warranting functional studies to further understand the etiology of sNSC.
doi:10.1038/ng.2463
PMCID: PMC3736322  PMID: 23160099
genome-wide association study; non-syndromic sagittal craniosynostosis; BMP2; BBS9; meta-analysis; nonsyndromic
5.  Hirschsprung’s disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation 
Journal of human genetics  2012;57(8):485-493.
Hirschsprung’s disease (HSCR) results from failed colonization of the embryonic gut by enteric neural crest cells (ENCCs); colonization requires RET proto-oncogene (RET) signaling. We sequenced RET to identify coding and splice-site variants in a population-based case group and we tested for associations between HSCR and common variants in RET and candidate genes (ASCL1, HOXB5, L1CAM, PHOX2B, PROK1, PROKR1) chosen because they are involved in ENCC proliferation, migration, and differentiation in animal models. We conducted a nested case-control study of 304 HSCR cases and 1 215 controls. Among 38 (12.5%) cases with 34 RET coding and splice-site variants, 18 variants were previously unreported. We confirmed associations with common variants in HOXB5 and PHOX2B but the associations with variants in ASCL1, L1CAM, and PROK1 were not significant after multiple comparisons adjustment. RET variants were strongly associated with HSCR (P values between 10−3 and 10−31) but this differed by race/ethnicity: associations were absent in African-Americans. Our population-based study not only identified novel RET variants in HSCR cases, it showed that common RET variants may not contribute to HSCR in all race/ethnic groups. The findings for HOXB5 and PHOX2B provide supportive evidence that genes regulating ENCC proliferation, migration, and differentiation could be risk factors for HSCR.
doi:10.1038/jhg.2012.54
PMCID: PMC3503526  PMID: 22648184
congenital abnormalities; enteric nervous system; Hirschsprung disease; RET
6.  Folate and Vitamin B12 Related Genes and Risk for Omphalocele 
Human Genetics  2011;131(5):739-746.
Both taking folic acid-containing vitamins around conception and consuming food fortified with folic acid have been reported to reduce omphalocele rates. Genetic factors are etiologically important in omphalocele as well; our pilot study showed a relationship with the folate metabolic enzyme gene methylenetetrahydrofolate reductase (MTHFR). We studied 169 non-aneuploid omphalocele cases and 761 unaffected, matched controls from all New York State births occurring between 1998 and 2005 to look for associations with single nucleotide polymorphisms (SNPs) known to be important in folate, vitamin B12, or choline metabolism. In the total study population, variants in the transcobalamin receptor gene (TCblR), rs2232775 (Q8R), and the MTHFR gene, rs1801131 (1298A>C), were significantly associated with omphalocele. In African-Americans significant associations were found with SNPs in genes for the vitamin B12 transporter (TCN2) and the vitamin B12 receptor (TCblR). A SNP in the homocysteine-related gene, betaine-homocysteine S-methyltransferase (BHMT), rs3733890 (R239Q), was significantly associated with omphalocele in both African-Americans and Asians. Only the TCblR association in the total population remained statistically significant if Bonferroni correction was applied. The finding that transcobalamin receptor (TCblR) and transporter (TCN2) SNPs and a BHMT SNP were associated with omphalocele suggests that disruption of methylation reactions, in which folate, vitamin B12, and homocysteine play critical parts, may be a risk factor for omphalocele. Our data, if confirmed, suggest that supplements containing both folic acid and vitamin B12 may be beneficial in preventing omphaloceles.
doi:10.1007/s00439-011-1117-3
PMCID: PMC3374579  PMID: 22116453
omphalocele; folate; vitamin B12; homocysteine; transcobalamin; transcobalamin receptor
7.  A SNCA Variant Associated with Parkinson’s Disease and Plasma α-Synuclein Level 
Archives of neurology  2010;67(11):1350-1356.
Objective
A functional repeat polymorphism in the SNCA promoter (REP1) conveys susceptibility for Parkinson’s disease (PD). There is also increasing evidence that SNPs elsewhere in the gene associate with risk. We sought to further explore the disease association, determine whether evidence of allelic heterogeneity exists, and examine the correlation between PD-associated variants and plasma α-synuclein levels.
Methods
We performed a two-tiered analysis of 1,956 PD patients and 2,112 controls from the NeuroGenetics Research Consortium using a comprehensive tagSNP approach. Previously published REP1 genotypes were also included. Plasma α-synuclein was assayed in 86 cases and 78 controls using a highly sensitive Luminex assay.
Results
Five of the 15 SNPs genotyped were associated with PD under an additive model in Tier 1 (α=0.05). Of these, four were successfully replicated in Tier 2. In the combined sample, the most significant marker was rs356219 (OR, 1.41; CI, 1.28–1.55; p = 1.6 × 10−12) located ~ 9 kb downstream from the gene. A regression model containing rs356219 alone best fit the data. The linkage disequilibrium correlation coefficient between this SNP and REP1 was low (r2=0.09). The risk-associated C allele of rs356219 was also correlated with higher transformed plasma α-synuclein levels in cases under an adjusted additive model (p = 0.005).
Conclusions
Our data suggest that one or more unidentified functional SNCA variants modify risk for PD, and that the effect is larger than, and independent of, REP1. This variant(s), tagged by rs356219, might act by upregulating SNCA expression in a dose-dependent manner.
doi:10.1001/archneurol.2010.279
PMCID: PMC3010848  PMID: 21060011
8.  Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson's Disease Modifier Gene via Interaction with Coffee 
PLoS Genetics  2011;7(8):e1002237.
Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's 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 SNP's 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.
Author Summary
Parkinson's disease (PD), like most common disorders, involves interactions between genetic make-up and environmental exposures that are unique to each individual. Caffeinated-coffee consumption may protect some people from developing PD, although not all benefit equally. In a genome-wide search, we discovered that variations in the glutamate-receptor gene GRIN2A modulate the risk of developing PD in heavy coffee drinkers. The study was hypothesis-free, that is, we cast a net across the entire genome allowing statistical significance to point us to a genetic variant, regardless of whether it fell in a genomic desert or an important gene. Fortuitously, the most significant finding was in a well-known gene, GRIN2A, which regulates brain signals that control movement and behavior. Our finding is important for three reasons: First, it is a proof of concept that studying genes and environment on the whole-genome scale is feasible, and this approach can identify important genes that are missed when environmental exposures are ignored. Second, the knowledge of interaction between GRIN2A, which is involved in neurotransmission in the brain, and caffeine, which is an adenosine-A2A-receptor antagonist, will stimulate new research towards understanding the cause and progression of PD. Third, the results may lead to personalized prevention of and treatment for PD.
doi:10.1371/journal.pgen.1002237
PMCID: PMC3158052  PMID: 21876681
9.  Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease 
Nature genetics  2010;42(9):781-785.
Parkinson disease (PD) is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study (GWAS) with 2000 PD and 1986 control Caucasian subjects from NeuroGenetics Research Consortium.1–5 We confirmed SNCA2,6–8 and MAPT3,7–9; replicated GAK9 (PPankratz+NGRC=3.2×10−9); and detected a novel association with HLA (PNGRC=2.9×10−8) which replicated in two datasets (PMeta-analysis=1.9×10−10). We designate the new PD genes PARK17 (GAK) and PARK18 (HLA). PD-HLA association was uniform across genetic and environmental risk strata, and strong in sporadic (P=5.5×10−10) and late-onset (P=2.4×10−8) PD. The association peak was at rs3129882, a non-coding variant in HLA-DRA. Two studies suggested rs3129882 influences expression of HLA-DR and HLA-DQ.10,11 PD brains exhibit up-regulation of DR antigens and presence of DR-positive reactive microglia.12 Moreover, non-steroidal anti-inflammatory drugs (NSAID) reduce PD risk.4,13 The genetic association with HLA coalesces the evidence for involvement of the immune system and offers new targets for drug development and pharmacogenetics.
doi:10.1038/ng.642
PMCID: PMC2930111  PMID: 20711177
10.  Visualizing Disease Associations: Graphic Analysis of Frequency Distributions as a Function of Age Using Moving Average Plots (MAP) with Application to Alzheimer's and Parkinson's Disease 
Genetic epidemiology  2010;34(1):92-99.
Age-related variation in marker frequency can be a confounder in association studies, leading to both false positive and false negative findings and subsequently to inconsistent reproducibility. We have developed a simple method, based on a novel extension of moving average plots (MAP), which allows investigators to inspect the frequency data for hidden age-related variations. MAP uses the standard case-control association data and generates a birds-eye view of the frequency distributions across the age spectrum; a picture in which one can see if, how, and when the marker frequencies in cases differ from that in controls. The marker can be specified as an allele, genotype, haplotype, or environmental factor; and age can be age at onset, age when subject was last known to be unaffected, or duration of exposure. Signature patterns that emerge can help distinguish true disease associations from spurious associations due to age effects, age-varying associations from associations that are uniform across all ages, and associations with risk from associations with age-at-onset. Utility of MAP is illustrated by application to genetic and epidemiological association data for Alzheimer's and Parkinson's disease. MAP is intended as a descriptive method, to complement standard statistical techniques. Although originally developed for age patterns, MAP is equally useful for visualizing any quantitative trait.
doi:10.1002/gepi.20439
PMCID: PMC2796703  PMID: 19582778
GWAS; MAPT; SNCA; APOE; coffee
11.  Association Analysis of MAPT H1 Haplotype and Subhaplotypes in Parkinson’s Disease 
Annals of neurology  2007;62(2):137-144.
Objective
An inversion polymorphism of approximately 900kb on chromosome 17q21, which includes the microtubule-associated protein tau (MAPT) gene defines two haplotype clades, H1 and H2. Several small case–control studies have observed a marginally significant excess of the H1/H1 diplotype among patients with Parkinson’s disease (PD), and one reported refining the association to a region spanning exons 1 to 4 of MAPT. We sought to replicate these findings.
Methods
We genotyped 1,762 PD patients and 2,010 control subjects for a single nucleotide polymorphism (SNP) that differentiates the H1 and H2 clades. We also analyzed four SNPs that define subhaplotypes within H1 previously reported to associate with PD or other neurodegenerative disorders.
Results
After adjusting for age, sex, and site, we observed a robust association between the H1/H1 diplotype and PD risk (odds ratio for H1/H1 vs H1/H2 and H2/H2, 1.46; 95% confidence interval, 1.25–1.69; p = 8 × 10−7). The effect was evident in both familial and sporadic subgroups, men and women, and early- and late-onset disease. Within H1/H1 individuals, there was no significant difference between cases and control subjects in the overall frequency distribution of H1 subhaplotypes.
Interpretation
Our data provide strong evidence that the H1 clade, which contains MAPT and several other genes, is a risk factor for PD. However, attributing this finding to variants within a specific region of MAPT is premature. Thorough fine-mapping of the H1 clade in large numbers of individuals is now needed to identify the underlying functional variant(s) that alter susceptibility for PD.
doi:10.1002/ana.21157
PMCID: PMC2836920  PMID: 17514749
12.  Lack of evidence for an association between UCHL1 S18Y and Parkinson’s disease 
UCHL1 has been proposed as a candidate gene for Parkinson’s disease (PD). A meta-analysis of white and Asian subjects reported an inverse association between the non-synonymous UCHL1 S18Y polymorphism and PD risk. However, this finding was not replicated in a large case–control study and updated meta-analysis restricted to white subjects. We performed a case–control study of 1757 PD patients recruited from movement disorder clinics and 2016 unrelated controls from four regions of the United States. All subjects self-reported as white. We did not observe evidence for an association between S18Y genotypes and PD (overall P-value for association: P = 0.42). After adjustment for age, sex, and recruitment region, the odds ratio for Y/S versus S/S was 0.91 (95% CI: 0.78–1.06) and for Y/Y versus S/S was 0.87 (95% CI: 0.58–1.29). We also did not observe a significant association for recessive or dominant models of inheritance, or after stratification by age at onset, age at blood draw, sex, family history of PD, or recruitment region. Our results suggest that UCHL1 S18Y is not a major susceptibility factor for PD in white populations although we cannot exclude the possibility that the S18Y variant exerts weak effects on risk, particularly in early-onset disease.
doi:10.1111/j.1468-1331.2007.02012.x
PMCID: PMC2823263  PMID: 18093156
case-control study; neuroepidemiology; Parkinson’s disease; UCHL1
13.  Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study 
Lancet Neurology  2008;7(7):583-590.
Summary
Background
Mutations in LRRK2, the gene that encodes leucine-rich repeat kinase 2, are a cause of Parkinson's disease (PD). The International LRRK2 Consortium was established to answer three key clinical questions: can LRRK2-associated PD be distinguished from idiopathic PD; which mutations in LRRK2 are pathogenic; and what is the age-specific cumulative risk of PD for individuals who inherit or are at risk of inheriting a deleterious mutation in LRRK2?
Methods
Researchers from 21 centres across the world collaborated on this study. The frequency of the common LRRK2 Gly2019Ser mutation was estimated on the basis of data from 24 populations worldwide, and the penetrance of the mutation was defined in 1045 people with mutations in LRRK2 from 133 families. The LRRK2 phenotype was defined on the basis of 59 motor and non-motor symptoms in 356 patients with LRRK2-associated PD and compared with the symptoms of 543 patients with pathologically proven idiopathic PD.
Findings
Six mutations met the consortium's criteria for being proven pathogenic. The frequency of the common LRRK2 Gly2019Ser mutation was 1% of patients with sporadic PD and 4% of patients with hereditary PD; the frequency was highest in the middle east and higher in southern Europe than in northern Europe. The risk of PD for a person who inherits the LRRK2 Gly2019Ser mutation was 28% at age 59 years, 51% at 69 years, and 74% at 79 years. The motor symptoms (eg, disease severity, rate of progression, occurrence of falls, and dyskinesia) and non-motor symptoms (eg, cognition and olfaction) of LRRK2-associated PD were more benign than those of idiopathic PD.
Interpretation
Mutations in LRRK2 are a clinically relevant cause of PD that merit testing in patients with hereditary PD and in subgroups of patients with PD. However, this knowledge should be applied with caution in the diagnosis and counselling of patients.
Funding
UK Medical Research Council; UK Parkinson's Disease Society; UK Brain Research Trust; Internationaal Parkinson Fonds; Volkswagen Foundation; National Institutes of Health: National Institute of Neurological Disorders and Stroke and National Institute of Aging; Udall Parkinson's Disease Centre of Excellence; Pacific Alzheimer Research Foundation Centre; Italian Telethon Foundation; Fondazione Grigioni per il Morbo di Parkinson; Michael J Fox Foundation for Parkinson's Research; Safra Global Genetics Consortium; US Department of Veterans Affairs; French Agence Nationale de la Recherche.
doi:10.1016/S1474-4422(08)70117-0
PMCID: PMC2832754  PMID: 18539534

Results 1-13 (13)