Association of GWAS loci with PD in China

Genome‐wide association studies (GWAS) have identified numerous single‐nucleotide polymorphisms (SNPs) at four loci (SNCA, PARK16, LRRK2, BST1) that can modulate the risk of Parkinson's disease (PD). The strength of these associations has yet to be clarified in Mainland China. Ethnic specific effect is an important consideration in GWAS analysis. Using a case–control methodology, we genotyped multiple SNPs at these four loci to investigate their association with risk of PD in Mainland China. A total of 1,146 study subjects comprising 636 patients with PD and 510 unrelated healthy controls were recruited. The minor alleles at SNPs rs894278, rs1994090, rs2046932, rs4698412, and rs7304279 were found to be significantly higher in cases than in controls, while the minor alleles were found to significantly reduce the risk of developing PD at SNPs rs823128, rs823156, rs6532194, rs1191532, and rs16856139. These associations remained after taking into considerations the effects of age and gender. We showed that multiple SNPs at LRRK2 and SNCA increase risk of PD, while PARK16 SNPs are associated with a lower risk of PD in China. Our study findings will contribute to further research using GWAS‐linked data and research on ethnic specific effect of common variants. © 2011 Wiley‐Liss, Inc.     

Genome-Wide association study identifies candidate genes for Parkinson's disease in an Ashkenazi Jewish population

Background

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.

Methods

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.

Results

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).

Conclusions

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.     

A Genome‐Wide Search for Type 2 Diabetes Susceptibility Genes in an Extended Arab Family

Twenty percent of people aged 20 to 79 have type 2 diabetes (T2D) in the United Arab Emirates (UAE). Genome‐wide association studies (GWAS) to identify genes for T2D have not been reported for Arab countries. We performed a discovery GWAS in an extended UAE family (N = 178; 66 diabetic; 112 healthy) genotyped on the Illumina Human 660 Quad Beadchip, with independent replication of top hits in 116 cases and 199 controls. Power to achieve genome‐wide significance (commonly P = 5 × 10^?8) was therefore limited. Nevertheless, transmission disequilibrium testing in FBAT identified top hits at Chromosome 4p12‐p13 (KCTD8: rs4407541, P = 9.70 × 10^?6; GABRB1: rs10517178/rs1372491, P = 4.19 × 10^?6) and 14q13 (PRKD1: rs10144903, 3.92 × 10^?6), supported by analysis using a linear mixed model approximation in GenABEL (4p12‐p13 GABRG1/GABRA2: rs7662743, P_adj‐agesex = 2.06 × 10^?5; KCTD8: rs4407541, P_adj‐agesex = 1.42 × 10^?4; GABRB1: rs10517178/rs1372491, P_adj‐agesex = 0.027; 14q13 PRKD1: rs10144903, P_adj‐agesex = 6.95 × 10^?5). SNPs across GABRG1/GABRA2 did not replicate, whereas more proximal SNPs rs7679715 (P_adj‐agesex = 0.030) and rs2055942 (P_adj‐agesex = 0.022) at COX7B2/GABRA4 did, in addition to a trend distally at KCTD8 (rs4695718: P_adj‐agesex = 0.096). Modelling of discovery and replication data support independent signals at GABRA4 (rs2055942: P_{adj‐agesex‐combined} = 3 × 10^?4) and at KCTD8 (rs4695718: P_{adj‐agesex‐combined} = 2 × 10^?4). Replication was observed for PRKD1 rs1953722 (proxy for rs10144903; P_adj‐agesex = 0.031; P_{adj‐agesex‐combined} = 2 × 10^?4). These genes may provide important functional leads in understanding disease pathogenesis in this population.     

Genetic Variation in the Peroxisome Proliferator‐Activated Receptor (PPAR) and Peroxisome Proliferator‐Activated Receptor Gamma Co‐activator 1 (PGC1) Gene Families and Type 2 Diabetes

We used a two‐stage study design to evaluate whether variations in the peroxisome proliferator‐activated receptors (PPAR) and the PPAR gamma co‐activator 1 (PGC1) gene families (PPARA, PPARG, PPARD, PPARGC1A, and PPARGC1B) are associated with type 2 diabetes (T2D) risk. Stage I used data from a genome‐wide association study (GWAS) from Shanghai, China (1019 T2D cases and 1709 controls) and from a meta‐analysis of data from the Asian Genetic Epidemiology Network for T2D (AGEN‐T2D). Criteria for selection of single nucleotide polymorphisms (SNPs) for stage II were: (1) P < 0.05 in single marker analysis in Shanghai GWAS and P < 0.05 in the meta‐analysis or (2) P < 10^?3 in the meta‐analysis alone and (3) minor allele frequency ≥ 0.10. Nine SNPs from the PGC1 family were assessed in stage II (an independent set of middle‐aged men and women from Shanghai with 1700 T2D cases and 1647 controls). One SNP in PPARGC1B, rs251464, was replicated in stage II (OR = 0.87; 95% CI: 0.77–0.99). Gene‐body mass index (BMI) and gene–exercise interactions and T2D risk were evaluated in a combined dataset (Shanghai GWAS and stage II data: 2719 cases and 3356 controls). One SNP in PPARGC1A, rs12640088, had a significant interaction with BMI. No interactions between the PPARGC1B gene and BMI or exercise were observed.     

Common obesity risk alleles in childhood attention‐deficit/hyperactivity disorder

Children with attention‐deficit/hyperactivity disorder (ADHD) have a higher rate of obesity than children without ADHD. Obesity risk alleles may overlap with those relevant for ADHD. We examined whether risk alleles for an increased body mass index (BMI) are associated with ADHD and related quantitative traits (inattention and hyperactivity/impulsivity). We screened 32 obesity risk alleles of single nucleotide polymorphisms (SNPs) in a genome‐wide association study (GWAS) for ADHD based on 495 patients and 1,300 population‐based controls and performed in silico analyses of the SNPs in an ADHD meta‐analysis comprising 2,064 trios, 896 independent cases, and 2,455 controls. In the German sample rs206936 in the NUDT3 gene (nudix; nucleoside diphosphate linked moiety X‐type motif 3) was associated with ADHD risk (OR: 1.39; P = 3.4 × 10^?4; P_corr = 0.01). In the meta‐analysis data we found rs6497416 in the intronic region of the GPRC5B gene (G protein‐coupled receptor, family C, group 5, member B; P = 7.2 × 10^?4; P_corr = 0.02) as a risk allele for ADHD. GPRC5B belongs to the metabotropic glutamate receptor family, which has been implicated in the etiology of ADHD. In the German sample rs206936 (NUDT3) and rs10938397 in the glucosamine‐6‐phosphate deaminase 2 gene (GNPDA2) were associated with inattention, whereas markers in the mitogen‐activated protein kinase 5 gene (MAP2K5) and in the cell adhesion molecule 2 gene (CADM2) were associated with hyperactivity. In the meta‐analysis data, MAP2K5 was associated with inattention, GPRC5B with hyperactivity/impulsivity and inattention and CADM2 with hyperactivity/impulsivity. Our results justify further research on the elucidation of the common genetic background of ADHD and obesity. © 2013 Wiley Periodicals, Inc.     

Association of ANK3 with bipolar disorder confirmed in East Asia

Results of genome‐wide association studies (GWASs) for bipolar disorder (BD) have indicated ANK3 as one of the most promising candidates for a susceptibility gene. In this study, we performed genetic association analysis of two single‐nucleotide polymorphisms (SNPs) in ANK3 (rs1938526 and rs10994336), whose genome‐wide significant associations were reported in a previous meta‐analysis of GWASs, using genotyping data of Korean and Japanese case–control samples and a part of data from a GWAS in Han‐Chinese from Taiwan. The total number of participants was 2,212 cases (352 from Korea, 860 from Japan, and 1,000 from Taiwan) and 2,244 controls (349 from Korea, 895 from Japan, and 1,000 from Taiwan). We could not detect any significant difference of allele frequency in individual analyses using each of the three populations. However, when we combined the three data sets and performed a meta‐analysis, rs1938526 showed nominally significant association (P = 0.048, odds ratio = 1.09). The over‐represented allele in BD was same as that reported in Caucasian GWASs. On the other hand, any significant association was not detected in rs10994336. This discrepancy between two SNPs may be explained by the different degree of linkage disequilibrium between Asian and Caucasian. These findings further supported the association between ANK3 and BD, and also suggested the genomic region around rs1938526 as a common risk locus across ethnicities. © 2011 Wiley‐Liss, Inc.     

Genome‐wide association study of theta band event‐related oscillations identifies serotonin receptor gene HTR7 influencing risk of alcohol dependence

Event‐related brain oscillations (EROs) represent highly heritable neuroelectrical correlates of human perception and cognitive performance that exhibit marked deficits in patients with various psychiatric disorders. We report the results of the first genome‐wide association study (GWAS) of an ERO endophenotype—frontal theta ERO evoked by visual oddball targets during P300 response in 1,064 unrelated individuals drawn from a study of alcohol dependence. Forty‐two SNPs of the Illumina HumanHap 1 M microarray were selected from the theta ERO GWAS for replication in family‐based samples (N = 1,095), with four markers revealing nominally significant association. The most significant marker from the two‐stage study is rs4907240 located within ARID protein 5A gene (ARID5A) on chromosome 2q11 (unadjusted, Fisher's combined P = 3.68 × 10^?6). However, the most intriguing association to emerge is with rs7916403 in serotonin receptor gene HTR7 on chromosome 10q23 (combined P = 1.53 × 10^?4), implicating the serotonergic system in the neurophysiological underpinnings of theta EROs. Moreover, promising SNPs were tested for association with diagnoses of alcohol dependence (DSM‐IV), revealing a significant relationship with the HTR7 polymorphism among GWAS case–controls (P = 0.008). Significant recessive genetic effects were also detected for alcohol dependence in both case–control and family‐based samples (P = 0.031 and 0.042, respectively), with the HTR7 risk allele corresponding to theta ERO reductions among homozygotes. These results suggest a role of the serotonergic system in the biological basis of alcohol dependence and underscore the utility of analyzing brain oscillations as a powerful approach to understanding complex genetic psychiatric disorders. © 2010 Wiley‐Liss, Inc.     

A case–control genome wide association study of substance use disorder (SUD) identifies novel variants on chromosome 7p14.1 in patients from the United Arab Emirates (UAE)

Genome wide association studies (GWASs) have provided insights into the molecular basis of the disorder in different population. This study presents the first GWAS of substance use disorder (SUD) in patients from the United Arab Emirates (UAE). The aim was to identify genetic association(s) that may provide insights into the molecular basis of the disorder. The GWAS discovery cohort consisted of 512 (250 cases and 262 controls) male participants from the UAE. Controls with no prior history of SUD were available from the Emirates family registry. The replication cohort consisted of 520 (415 cases and 105 controls) Australian male Caucasian participants. The GWAS discovery samples were genotyped for 4.6 million single nucleotide polymorphism (SNP). The replication cohort was genotyped using TaqMan assay. The GWAS association analysis identified three potential SNPs rs118129027 (p‐value = 6.24 × 10^?8), rs74477937 (p‐value = 8.56 × 10^?8) and rs78707086 (p‐value = 8.55 × 10^?8) on ch7p14.1, that did not meet the GWAS significance threshold but were highly suggestive. In the replication cohort, the association of the three top SNPs did not reach statistical significance. In a meta‐analysis of the discovery and the replication cohorts, there were no strengthen evidence for association of the three SNPs. The top identified rs118129027 overlaps with a regulatory factor (enhancer) region that targets three neighboring genes LOC105375237, LOC105375240, and YAE1D1. The YAE1D1, which represents a potential locus that is involved in regulating translation initiation pathway. Novel associations that require further confirmation were identified, suggesting a new insight to the genetic basis of SUD.     

Common variants in DLG1 locus are associated with non‐syndromic cleft lip with or without cleft palate

Non‐syndromic cleft lip with or without cleft palate (nsCL/P) is a common craniofacial anomaly with a complex and heterogeneous aetiology. Knowledge regarding specific genetic factors underlying this birth defect is still not well understood. Therefore, we conducted an independent replication analysis for the top‐associated variants located within the DLG1 locus at chromosome 3q29, which was identified as a novel cleft‐susceptibility locus in our genome‐wide association study (GWAS). Mega‐analysis of the pooled individual data from the GWAS and replication study confirmed that common DLG1 variants are associated with the risk of nsCL/P. Two single nucleotide polymorphisms (SNPs), rs338217 and rs7649443, were statistically significant even at the genome‐wide level (P_trend = 9.70E?10 and P_trend = 8.96E?09, respectively). Three other SNPs, rs9826379, rs6805920 and rs6583202, reached a suggestive genome‐wide significance threshold (P_trend < 1.00E?05). The location of the strongest individual SNP in the intronic sequence of the gene encoding DLG1 antisense RNA suggests that the true causal variant implicated in the risk of nsCL/P may affect the DLG1 gene expression level rather than structure of the encoded protein. In conclusion, we identified a novel cleft‐susceptibility locus at chromosome 3q29 with a DLG1 as a novel candidate gene for this common craniofacial anomaly.     

Genome‐wide compound heterozygosity analysis highlighted 4 novel susceptibility loci for congenital heart disease in Chinese population

Genome‐wide association studies (GWASs) have achieved great success in deciphering the genetic cause of congenital heart disease (CHD). However, the heritability of CHD remains to be clarified, and numerous genetic factors responsible for occurrence of CHD are yet unclear. In this study, we performed a genome‐wide search for relaxed forms of compound heterozygosity (CH) in association with CHD using our existing GWAS data including 2265 individuals (957 CHD cases and 1308 controls). CollapsABEL was used to iteratively test the association between the CH genotype and the CHD phenotype in a sliding window manner. We highlighted 17 genetic loci showing suggestive CH‐like associations with CHD (P < 5 × 10^?8), among which 4 genetic loci had expression quantitative trait loci (eQTL) effects in blood (P_eQTL < 0.01). After conditional association analysis, each loci had only 1 independently effective signal reaching the significance threshold (rs2071477/rs3129299 at 6p21.32, P = 2.47 × 10^?10; rs10773097/rs2880921 at 12q24.31, P = 3.30 × 10^?8; rs73032040/rs7259476 at 19q13.11, P = 1.14 × 10^?8; rs10416386/rs4239517 at 19q13.31, P = 1.15 × 10^?9), together explained 7.83% of the CHD variance. Among these 4 associated loci, outstanding candidates for CHD‐associated genes included UBC, CFM2, ZNF302, LYPD3 and CADM4. Although replication studies with larger sample size are warranted, the first CH GWAS of CHD may extend our current knowledge of the genetic contributions to CHD in the Han Chinese population.     

Genome‐wide analyses of psychological resilience in U.S. Army soldiers

Though a growing body of preclinical and translational research is illuminating a biological basis for resilience to stress, little is known about the genetic basis of psychological resilience in humans. We conducted genome‐wide association studies (GWASs) of self‐assessed (by questionnaire) and outcome‐based (incident mental disorders from predeployment to postdeployment) resilience among European (EUR) ancestry soldiers in the Army study to assess risk and resilience in servicemembers. Self‐assessed resilience (N = 11,492) was found to have significant common‐variant heritability (h² = 0.162, se = 0.050, p = 5.37 × 10^?4), and to be significantly negatively genetically correlated with neuroticism (r_g = ?0.388, p = .0092). GWAS results from the EUR soldiers revealed a genome‐wide significant locus on an intergenic region on Chr 4 upstream from doublecortin‐like kinase 2 (DCLK2) (four single nucleotide polymorphisms (SNPs) in LD; top SNP: rs4260523 [p = 5.65 × 10^?9] is an eQTL in frontal cortex), a member of the doublecortin family of kinases that promote survival and regeneration of injured neurons. A second gene, kelch‐like family member 36 (KLHL36) was detected at gene‐wise genome‐wide significance [p = 1.89 × 10^?6]. A polygenic risk score derived from the self‐assessed resilience GWAS was not significantly associated with outcome‐based resilience. In very preliminary results, genome‐wide significant association with outcome‐based resilience was found for one locus (top SNP: rs12580015 [p = 2.37 × 10^?8]) on Chr 12 downstream from solute carrier family 15 member 5 (SLC15A5) in subjects (N = 581) exposed to the highest level of deployment stress. The further study of genetic determinants of resilience has the potential to illuminate the molecular bases of stress‐related psychopathology and point to new avenues for therapeutic intervention.     

Addressing Population‐Specific Multiple Testing Burdens in Genetic Association Studies

The number of effectively independent tests performed in genome‐wide association studies (GWAS) varies by population, making a universal P‐value threshold inappropriate. We estimated the number of independent SNPs in Phase 3 HapMap samples by: (1) the LD‐pruning function in PLINK, and (2) an autocorrelation‐based approach. Autocorrelation was also used to estimate the number of independent SNPs in whole genome sequences from 1000 Genomes. Both approaches yielded consistent estimates of numbers of independent SNPs, which were used to calculate new population‐specific thresholds for genome‐wide significance. African populations had the most stringent thresholds (1.49 × 10^?7 for YRI at r² = 0.3), East Asian populations the least (3.75 × 10^?7 for JPT at r² = 0.3). We also assessed how using population‐specific significance thresholds compared to using a single multiple testing threshold at the conventional 5 × 10^?8 cutoff. Applied to a previously published GWAS of melanoma in Caucasians, our approach identified two additional genes, both previously associated with the phenotype. In a Chinese breast cancer GWAS, our approach identified 48 additional genes, 19 of which were in or near genes previously associated with the phenotype. We conclude that the conventional genome‐wide significance threshold generates an excess of Type 2 errors, particularly in GWAS performed on more recently founded populations.     

Genome‐wide association study of shared liability to anxiety disorders in Army STARRS

Anxiety disorders (ANX), namely generalized anxiety, panic disorder, and phobias, are common, etiologically complex syndromes that show increasing prevalence and comorbidity throughout adolescence and beyond. Few genome‐wide association studies (GWAS) examining ANX risk have been published and almost exclusively in individuals of European ancestry. In this study, we phenotyped participants from the Army Study To Assess Risk and Resilience in Servicemembers (STARRS) to approximate DSM‐based ANX diagnoses. We factor‐analyzed those to create a single dimensional anxiety score for each subject. GWAS were conducted using that score within each of three ancestral groups (EUR, AFR, LAT) and then meta‐analyzed across ancestries (N_Total = 16,510). We sought to (a) replicate prior ANX GWAS findings in ANGST; (b) determine whether results extended to other ancestry groups; and (c) meta‐analyze with ANGST for increased power to identify novel susceptibility loci. No reliable genome‐wide significant SNP associations were detected in STARRS. However, SNPs within the CAMKMT gene located in region 2p21 associated with shared ANX risk in ANGST were replicated in EUR soldiers but not other ancestry groups. Combining EUR STARRS and ANGST (N = 28,950) yielded a more robust 2p21 association signal (p = 9.08x10^?11). Gene‐based analyses supported three genes within 2p21 and LBX1 on chromosome 10. More powerful ANX genetic studies will be required to identify further loci.     

HLA‐DRA is associated with Parkinson's disease in Iranian population

The rs3129882, a noncoding variant in HLA‐DR, was found to be associated with Parkinson's disease (PD) using several genome‐wide association studies. The aim of this replication study was to explore the relationship between this variant and PD in Iranian population. Genomic DNA was extracted from peripheral blood samples, and the rs3129882 SNP was genotyped using a PCR‐RFLP method in 520 PD patients and 520 healthy Iranian controls. Significant differences were found in allele frequencies between patients and controls (χ² = 4.64, P = 0.031). Under additive and dominant models, the association of the SNP with PD risk is significant, where the A allele was observed to be protective. The results suggest that rs3129882 polymorphism may be a risk factor for PD in Iranian. This is the first study reporting such an association in this population. More replication studies are needed to confirm this data.     

Replication study of genome‐wide associated SNPs with late‐onset Alzheimer's disease

Late‐onset Alzheimer's disease (LOAD) is a multifactorial disease with the potential involvement of multiple genes. Four recent genome‐wide association studies (GWAS) have found variants showing significant association with LOAD on chromosomes 6, 10, 11, 12, 14, 18, 19, and on the X chromosome. We examined a total of 12 significant SNPs from these studies to determine if the results could be replicated in an independent large case–control sample. We genotyped these 12 SNPs as well the E2/E3/E4 APOE polymorphisms in up to 993 Caucasian Americans with LOAD and up to 976 age‐matched healthy Caucasian Americans. We found no statistically significant associations between the 12 SNPs and the risk of AD. Stratification by APOE*4 carrier status also failed to reveal statistically significant associations. Additional analyses were performed to examine potential associations between the 12 SNPs and age‐at‐onset (AAO) and disease duration among AD cases. Significant associations were observed between AAO and ZNF224/rs3746319 (P = 0.002) and KCNMA1/rs16934131 (P = 0.0066). KCNMA1/rs16934131 also demonstrated statistically significant association with disease duration (P = 0.0002). Although we have been unable to replicate the reported GWAS association with AD risk in our sample, we have identified two new associations with AAO and disease duration that need to be confirmed in additional studies. © 2011 Wiley‐Liss, Inc.     

Variants in BAK1, SPRY4, and GAB2 are associated with pediatric germ cell tumors: A report from the children's oncology group

Germ cell tumors (GCT) are a rare form of childhood cancer that originate from the primordial germ cell. Recent genome‐wide association studies (GWAS) have identified susceptibility alleles for adult testicular GCT (TGCT). We test whether these SNPs are associated with GCT in pediatric and adolescent populations. This case‐parent triad study includes individuals with GCT diagnosed between ages 0 and 19. We evaluated 26 SNPs from GWAS of adult TGCT and estimated main effects for pediatric GCT within complete trios (N = 366) using the transmission disequilibrium test. We used Estimation of Maternal, Imprinting and interaction effects using Multinomial modelling to evaluate maternal effects in non‐Hispanic white trios and dyads (N = 244). We accounted for multiple comparisons using a Bonferroni correction. A variant in SPRY4 (rs4624820) was associated with reduced risk of GCT (OR [95% CI]: 0.70 [0.57, 0.86]). A variant in BAK1 (rs210138) was positively associated with GCT (OR [95% CI]: 1.70 [1.32, 2.18]), with a strong estimated effect for testis tumors (OR [95% CI]: 3.31 [1.89, 5.79]). Finally, a SNP in GAB2 (rs948662) was associated with increased risk for GCT (OR [95% CI]: 1.56 [1.20, 2.03]). Nominal associations (P < 0.05) were noted for eight additional loci. A maternal effect was observed for KITLG SNP rs4474514 (OR [95% CI]: 1.66 [1.21, 2.28]) and a paternal parent‐of‐origin effect was observed for rs7221274 (P = 0.00007), near TEX14, RAD51C, and PPM1E. We observed associations between SNPs in SPRY4, BAK1, and GAB2 and GCTs. This analysis suggests there may be common genetic risk factors for GCT in all age groups.     

Genetic Variants in MicroRNAs and Their Binding Sites Are Associated with the Risk of Parkinson Disease

MicroRNAs (miRNAs) are small noncoding RNAs that serve as key regulators of gene expression. They have been shown to be involved in a wide range of biological processes including neurodegenerative diseases. Genetic variants in miRNAs or miRNA‐binding sites on their target genes could affect miRNA function and contribute to disease risk. Here, we investigated the association of miRNA‐related genetic variants with Parkinson disease (PD) using data from the largest GWAS on PD. Of 243 miRNA variants, we identified rs897984:T>C in miR‐4519 (P value = 1.3×10^?5 and OR = 0.93) and rs11651671:A>G in miR‐548at‐5p (P value = 1.1×10^?6 and OR = 1.09) to be associated with PD. We showed that the variant's mutant alleles change the secondary structure and decrease expression level of their related miRNAs. Subsequently, we highlighted target genes that might mediate the effects of miR‐4519 and miR‐548at‐5p on PD. Among them, we experimentally showed that NSF is a direct target of miR‐4519. Furthermore, among 48,844 miRNA‐binding site variants, we found 32 variants (within 13 genes) that are associated with PD. Four of the host genes, CTSB, STX1B, IGSF9B, and HSD3B7, had not previously been reported to be associated with PD. We provide evidence supporting the potential impact of the identified miRNA‐binding site variants on miRNA‐mediated regulation of their host genes.     

Evaluation of risk loci for schizophrenia derived from genome‐wide association studies in a German population

In the genome‐wide association study (GWAS) on schizophrenia [O'Donovan et al. (2008); Nat Genet 40:1053–1055] a UK‐sample of 479 cases with DSM‐IV schizophrenia was genotyped in comparison to control subjects with follow up of 12 putative loci in international replication sets of approximately 15,000 cases and controls. In these cohorts and a combined bipolar and schizophrenia UK‐sample, six single nucleotide polymorphisms (SNPs) supported association, with the strongest evidence for SNP‐marker rs1344706 at the zinc finger ZNF804A locus on chromosome 2q32.1 (P = 1.61 × 10^?7). We attempted replication of these findings in a German population of 2,154 individuals (632 with affective disorders, 937 with schizophrenia, and 585 controls), but found none of the GWAS risk alleles significantly associated with psychosis. Particularly rs1344706, initially surpassing the genome‐wide significance level in an extended phenotype of schizophrenia and affective disorder, produced consistently negative results. At the ZNF804A locus estimated Odds ratios reached 1.08 (0.93–1.26 95% CI) for the schizophrenia sample and 1.04 (0.90–1.20 95% CI) for the combined set of cases with schizophrenia and affective disorder. The main limitation of our study may be the reduced power of the sample size, but our data may be useful for future meta‐analysis of GWA data sets. Although GWAS have proven extraordinary successful in identifying susceptibility genes for complex genetic disorders, the hypothesis of common genetic variants in the complex group of the schizophrenic psychoses with small effect size but relatively high frequency is still put to further scrutiny. © 2011 Wiley‐Liss, Inc.     

Allelic imbalance of expression and epigenetic regulation within the alpha‐synuclein wild‐type and p.Ala53Thr alleles in Parkinson disease

Genetic alterations in the alpha‐synuclein (SNCA) gene have been implicated in Parkinson Disease (PD), including point mutations, gene multiplications, and sequence variations within the promoter. Such alterations may be involved in pathology through structural changes or overexpression of the protein leading to protein aggregation, as well as through impaired gene expression. It is, therefore, of importance to specify the parameters that regulate SNCA expression in its normal and mutated state. We studied the expression of SNCA alleles in a lymphoblastoid cell line and in the blood cells of a patient heterozygous for p.Ala53Thr, the first mutation to be implicated in PD pathogenesis. Here, we provide evidence that: (1) SNCA shows monoallelic expression in this patient, (2) epigenetic silencing of the mutated allele involves histone modifications but not DNA methylation, and (3) steady‐state mRNA levels deriving from the normal SNCA allele in this patient exceed those of the two normal SNCA alleles combined, in matching, control individuals. An imbalanced SNCA expression in this patient is thus documented, with silencing of the p.Ala53Thr allele and upregulation of the wild‐type‐allele. This phenomenon is demonstrated for a first time in the SNCA gene, and may have important implications for PD pathogenesis. Hum Mutat 31:1–7, 2010. © 2010 Wiley‐Liss, Inc.