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.     

Association study of Nogo‐related genes with schizophrenia in a Japanese case–control sample

Many studies have suggested that myelin dysfunction may be causally involved in the pathogenesis of schizophrenia. Nogo (RTN4), myelin‐associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMG) all bind to the common receptor, Nogo‐66 receptor 1 (RTN4R). We examined 68 single nucleotide polymorphisms (SNPs) (51 with genotyping and 17 with imputation analysis) from these four genes for genetic association with schizophrenia, using a 2,120 case–control sample from the Japanese population. Allelic tests showed nominally significant association of two RTN4 SNPs (P = 0.047 and 0.037 for rs11894868 and rs2968804, respectively) and two MAG SNPs (P = 0.034 and 0.029 for rs7249617 and rs16970218, respectively) with schizophrenia. The MAG SNP rs7249617 also showed nominal significance in a genotypic test (P = 0.017). In haplotype analysis, the MAG haplotype block including rs7249617 and rs16970218 showed nominal significance (P = 0.008). These associations did not remain significant after correction for multiple testing, possibly due to their small genetic effect. In the imputation analysis of RTN4, the untyped SNP rs2972090 showed nominally significant association (P = 0.032) and several imputed SNPs showed marginal associations. Moreover, in silico analysis (PolyPhen) of a missense variant (rs11677099: Asp357Val), which is in strong linkage disequilibrium with rs11894868, predicted a deleterious effect on Nogo protein function. Despite a failure to detect robust associations in this Japanese cohort, our nominally positive signals, taken together with previously reported biological and genetic findings, add further support to the “disturbed myelin system theory of schizophrenia” across different populations. © 2011 Wiley‐Liss, Inc.     

Genetic meta‐analysis of obsessive–compulsive disorder and self‐report compulsive symptoms

We investigated whether obsessive–compulsive (OC) symptoms from a population‐based sample could be analyzed to detect genetic variants influencing obsessive–compulsive disorder (OCD). We performed a genome‐wide association studies (GWAS) on the obsession (rumination and impulsions) and compulsion (checking, washing, and ordering/precision) subscales of an abbreviated version of the Padua Inventory (N = 8,267 with genome‐wide genotyping and phenotyping). The compulsion subscale showed a substantial and significant positive genetic correlation with an OCD case–control GWAS (r _G = 0.61, p = .017) previously published by the Psychiatric Genomics Consortium (PGC‐OCD). The obsession subscale and the total Padua score showed no significant genetic correlations (r _G = ?0.02 and r _G = 0.42, respectively). A meta‐analysis of the compulsive symptoms GWAS with the PGC‐OCD revealed no genome‐wide significant Single‐Nucleotide Polymorphisms (SNPs combined N = 17,992, indicating that the power is still low for individual SNP effects). A gene‐based association analysis, however, yielded two novel genes (WDR7 and ADCK1). The top 250 genes in the gene‐based test also showed a significant increase in enrichment for psychiatric and brain‐expressed genes. S‐Predixcan testing showed that for genes expressed in hippocampus, amygdala, and caudate nucleus significance increased in the meta‐analysis with compulsive symptoms compared to the original PGC‐OCD GWAS. Thus, the inclusion of dimensional symptom data in genome‐wide association on clinical case–control GWAS of OCD may be useful to find genes for OCD if the data are based on quantitative indices of compulsive behavior. SNP‐level power increases were limited, but aggregate, gene‐level analyses showed increased enrichment for brain‐expressed genes related to psychiatric disorders, and increased association with gene expression in brain tissues with known emotional, reward processing, memory, and fear‐formation functions.     

Family‐based genetic association study of DLGAP3 in Tourette Syndrome

Tourette syndrome (TS) is a childhood‐onset neuropsychiatric disorder that is familial and highly heritable. Although genetic influences are thought to play a significant role in the development of TS, no definite TS susceptibility genes have been identified to date. TS is believed to be genetically related to both obsessive‐compulsive disorder (OCD) and grooming disorders (GD) such as trichotillomania (TTM). SAP90/PSD95‐associated protein 3 (SAPAP3/DLGAP3) is a post‐synaptic scaffolding protein that is highly expressed in glutamatergic synapses in the striatum and has recently been investigated as a candidate gene in both OCD and GD studies. Given the shared familial relationship between TS, OCD and TTM, DLGAP3 was evaluated as a candidate TS susceptibility gene. In a family‐based sample of 289 TS trios, 22 common single nucleotide polymorphisms (SNPs) in the DLGAP3 region were analyzed. Nominally significant associations were identified between TS and rs11264126 and two haplotypes containing rs11264126 and rs12141243. Secondary analyses demonstrated that these results cannot be explained by the presence of comorbid OCD or TTM in the sample. Although none of these results remained significant after correction for multiple hypothesis testing, DLGAP3 remains a promising candidate gene for TS. © 2010 Wiley‐Liss, Inc.     

Associations of the 5‐hydroxytryptamine (serotonin) Receptor 1B gene (HTR1B) with alcohol,cocaine, and heroin abuse

Abnormal serotonergic pathways are implicated in numerous neuropsychiatric disorders including alcohol and drug dependence (abuse). The human 5‐hydroxytryptamine (serotonin) receptor 1B, encoded by the HTR1B (5‐HT1B) gene, is a presynaptic serotonin autoreceptor that plays an important role in regulating serotonin synthesis and release. Although there was evidence of associations of the HTR1B gene variants in the etiologies of substance use disorders, negative findings were also reported. To clarify the roles of commonly reported single nucleotide polymorphisms (SNPs) of the HTR1B gene underlying alcohol and drug dependence (abuse), we performed a meta‐analysis based on the available genotype data from individual candidate gene‐based association studies. Evidence of association was found between the functional SNP ?161A>T (rs130058) and alcohol, cocaine, and heroin dependence (e.g., P = 0.03 and odds ratio (OR) = 1.2 (1.02, 1.42) in the combined European, Asian, African, and Hispanic populations). SNP ?261T>G (rs11568817) also showed evidence of association but with different directions in Europeans and non‐Europeans (e.g., P = 0.0018 with OR = 1.42 (1.14, 1.76) and P = 0.01 with ORs = 0.5 (0.3, 0.85), respectively). This meta‐analysis supports the associations of HTR1B ?261T>G and ?161A>T with alcohol and drug abuse and further investigations are warranted in larger samples. © 2013 Wiley Periodicals, Inc.     

Association of SLC6A12 variants with aspirin‐intolerant asthma in a Korean population

Aspirin‐intolerant asthma (AIA) occurs from asthma exacerbation after exposure to aspirin. However, the underlying mechanisms of AIA occurrence are still unclear. The critical role of the solute carrier family 6 (neurotransmitter transporter, betaine/GABA) member 12 (SLC6A12) gene in GABAergic transmission, which is associated with mucus production in asthma, makes it a candidate gene for AIA association study. Eight single nucleotide polymorphisms (SNPs) in SLC6A12 were genotyped in 163 aspirin‐intolerant asthma (AIA) and 429 aspirin‐tolerant asthma (ATA) patients of Korean ethnicity. Associations between polymorphisms of SLC6A12 and AIA were analysed using multivariate logistic analysis. Results showed that two polymorphisms and a haplotype in SLC6A12, rs499368 (P= 0.005; P^corr= 0.03), rs557881 (non‐synonymous C10R, P= 0.007; P^corr= 0.04), and SLC6A12_BL1_ht1 (P= 0.009; P^corr= 0.05) respectively, were significantly associated with AIA after multiple testing corrections. In addition, SNPs of SLC6A12 were significantly associated with the fall rate of FEV₁ by aspirin provocation suggesting that SLC6A12 could affect reversibility of lung function abnormalities in AIA patients. Although these results are preliminary and future replications are needed to confirm these findings, this study showed evidence of association between variants in SLC6A12 and AIA occurrence among asthmatics in a Korean population.     

Trans‐Ethnic Meta‐Analysis Identifies Common and Rare Variants Associated with Hepatocyte Growth Factor Levels in the Multi‐Ethnic Study of Atherosclerosis (MESA)

Hepatocyte growth factor (HGF) is a mesenchyme‐derived pleiotropic factor that regulates cell growth, motility, mitogenesis, and morphogenesis in a variety of cells, and increased serum levels of HGF have been linked to a number of clinical and subclinical cardiovascular disease phenotypes. However, little is currently known regarding which genetic factors influence HGF levels, despite evidence of substantial genetic contributions to HGF variation. Based upon ethnicity‐stratified single‐variant association analysis and trans‐ethnic meta‐analysis of 6201 participants of the Multi‐Ethnic Study of Atherosclerosis (MESA), we discovered five statistically significant common and low‐frequency variants: HGF missense polymorphism rs5745687 (p.E299K) as well as four variants (rs16844364, rs4690098, rs114303452, rs3748034) within or in proximity to HGFAC. We also identified two significant ethnicity‐specific gene‐level associations (A1BG in African Americans; FASN in Chinese Americans) based upon low‐frequency/rare variants, while meta‐analysis of gene‐level results identified a significant association for HGFAC. However, identified single‐variant associations explained modest proportions of the total trait variation and were not significantly associated with coronary artery calcium or coronary heart disease. Our findings indicate that genetic factors influencing circulating HGF levels may be complex and ethnically diverse.     

ABCA1 rs4149313 Polymorphism and Susceptibility to Coronary Heart Disease: A Meta‐Analysis

Many existing studies have demonstrated that common polymorphisms in the ABCA1 gene may play important roles in the development and progression of coronary heart disease (CHD), but individually published results are inconclusive. This meta‐analysis aimed to derive a more precise estimation of the relationship between the ABCA1 rs4149313 polymorphism and CHD risk. We searched the CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from inception through 1 September 2013. Meta‐analysis was performed using the STATA 12.0 software. Odds ratios (OR) and their 95% confidence intervals (CI) were estimated. Eleven case‐control studies were included with a total of 5416 CHD patients and 20,897 healthy controls. Our meta‐analysis results revealed that the ABCA1 rs4149313 polymorphism may be associated with an increased risk of CHD. Subgroup analysis by ethnicity suggested that there were significant associations between the ABCA1 rs4149313 polymorphism and an increased risk of CHD in Asian populations, but not in Caucasian populations (all P > 0.05). Meta‐regression analyses showed that ethnicity may be a main source of heterogeneity. The present meta‐analysis suggests that the ABCA1 rs4149313 polymorphism may contribute to the risk of CHD, especially in Asian populations.     

Association of Interleukin 10 Gene Polymorphisms with Autoimmune Thyroid Disease: Meta‐Analysis

The aim of this study was to perform a meta‐analysis of eligible studies and to derive a precise estimate of the association between interleukin 10 (IL10) polymorphisms and susceptibility to autoimmune thyroid disease (AITD). Meta‐analyses were conducted on the associations between AITD and the ‐1082 G/A (rs1800896), ‐819 C/T (rs1800871) and ‐592 C/A (rs1800872) polymorphisms in IL10, and the haplotype of these polymorphisms and AITD. A total of 2903 AITD patients and 3060 controls in 10 eligible studies were included in the meta‐analysis. This meta‐analysis showed significant associations between IL10 at the ‐1082 G allele and overall AITD (OR: 1.44, 95% CI 1.13–1.82, P = 0.003), but no association between the IL10 ‐592 C allele and the ‐819 C allele and AITD. Subgroup studies demonstrated significant associations between the ‐1082 G allele and susceptibility to Graves’ disease. Ethnicity‐specific meta‐analysis revealed significant associations between the ‐1082 G allele and AITD susceptibility in Asian populations; however, in Middle Eastern populations, no association was evident. Meta‐analysis of the IL10 haplotype revealed an association between the ATA haplotype and AITD (OR: 1.17, 95% CI 1.00–1.36, P = 0.04). Meta‐analysis demonstrates that the IL10 polymorphisms are associated with susceptibility to AITD.     

Post‐Genome‐Wide Association Study Challenges for Lipid Traits: Describing Age as a Modifier of Gene‐Lipid Associations in the Population Architecture Using Genomics and Epidemiology (PAGE) Study

Numerous common genetic variants that influence plasma high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol (LDL‐C), and triglyceride distributions have been identified via genome‐wide association studies (GWAS). However, whether or not these associations are age‐dependent has largely been overlooked. We conducted an association study and meta‐analysis in more than 22,000 European Americans between 49 previously identified GWAS variants and the three lipid traits, stratified by age (males: <50 or ≥50 years of age; females: pre‐ or postmenopausal). For each variant, a test of heterogeneity was performed between the two age strata and significant P_het values were used as evidence of age‐specific genetic effects. We identified seven associations in females and eight in males that displayed suggestive heterogeneity by age (P_het < 0.05). The association between rs174547 (FADS1) and LDL‐C in males displayed the most evidence for heterogeneity between age groups (P_het = 1.74E‐03, I² = 89.8), with a significant association in older males (P = 1.39E‐06) but not younger males (P = 0.99). However, none of the suggestive modifying effects survived adjustment for multiple testing, highlighting the challenges of identifying modifiers of modest SNP‐trait associations despite large sample sizes.     

Association between polymorphisms in catechol‐O‐methyltransferase (COMT) and cocaine‐induced paranoia in European‐American and African‐American populations

Catechol‐O‐methyltransferase (genetic locus, COMT) is a major enzyme involved in catecholamine metabolism and has been associated with numerous psychiatric phenotypes. We studied COMT SNPs and haplotypes in cocaine‐induced paranoia (CIP) in African‐American (AA) and European‐American (EA) populations. We genotyped 17 SNPs across the COMT locus in 319 AA pedigrees (848 individuals) and 302 EA pedigrees (707 individuals). Family‐controlled association analyses were conducted using FBAT. We found SNP rs737865 to be nominally significantly associated in the AA family population (P = 0.05). In EAs, the best‐known marker, rs4680 (Val158Met), was nominally significant in additive models (P = 0.03). SNP rs174696 also showed nominal significance in additive models (P = 0.02). We considered the three SNPs (rs737866–rs4680–rs174696) together in haplotype analysis in both family populations, using HBAT. The A–A–T haplotype was significantly associated with CIP in EAs (Z = 2.845; P = 0.0044, global P = 0.020). We then studied COMT SNPs in an additional 738 AA and 404 EA unrelated cocaine dependent individuals with and without paranoia. The A–A–T haplotype was significantly associated to CIP in the AA unrelated population (P = 0.0015). Two haplotypes, A–G–C and A–A–C, were significant in the EA unrelated population (P = 0.001 and 0.0003). We also identified rs4680 and three other SNPs, rs933271, rs5993883, and rs740603, as potentially functional variants, as predicted by a signature of positive selection in unrelated EAs and AAs. Based on our robust family‐controlled and unrelated‐affected analyses, we conclude that COMT is associated with CIP, possibly as a result of its role in the metabolism of dopamine and norepinephrine. © 2011 Wiley‐Liss, Inc.     

Association of rs11643718 SLC12A3 and rs741301 ELMO1 Variants with Diabetic Nephropathy in South Indian Population

This study reports on the association of genetic variants selected from previous genome‐wide association studies for type 2 diabetic nephropathy in south Indians. Eight variants were genotyped in 601 type 2 diabetic subjects without nephropathy (DM) and 583 type 2 diabetic subjects with nephropathy (DN) by MassARRAY. The minor allele frequencies of rs11643718 SLC12A3 variant and rs741301 ELMO1 variant were significantly different between DM and DN groups (P = 0.029 and 0.016, respectively). A combined analysis showed that the subjects carrying the risk genotypes of both these variants (GG of rs11643718 + AG/AA of rs741301) had a significant association with DN with an odds ratio [adjusted for age, sex, Body Mass Index (BMI), HbA1c, and systolic Blood Pressure (BP)] of 1.73 (1.30–2.30, P = 1.72 × 10^–4) as compared to subjects carrying all other genotype combinations. This is the first study to report a significant association of the SLC12A3 rs11643718 and ELMO1 rs741301 (Single nucleotide Polymorphism) SNPs with diabetic nephropathy in south Indians.     

The Impact of FOXP3 Polymorphism on the Risk of Allergic Rhinitis: A Meta‐Analysis

Polymorphisms of several genes were reported to be associated with the risk of allergic rhinitis. Here, we first conducted a meta‐analysis to evaluate the potential genetic association between the polymorphisms of the FOXP3 (Forkhead Box P3) gene and the susceptibility to allergic rhinitis. A total of 2671 relevant articles were initially retrieved from the databases of PubMed, Web of Science, Embase, WANFANG/CNKI and Scopus, and six eligible case‐control studies were finally enrolled in our meta‐analysis, according to our strict inclusion/exclusion criteria. Based on the extracted data, Mantel–Haenszel statistic, Cochrane's Q statistic, I² test, subgroup meta‐analysis, Begg's test, Egger's test and sensitivity analysis were performed via Stata/SE 12.0 software. The results of the Mantel–Haenszel statistic regarding rs3761548 showed that no significant difference was observed in the allergic rhinitis case and population‐based control group under the genetic models of A versus C, AA versus CC, CA+AA versus CC, AA versus CC+CA and carrier A versus C (all P‐value of Association Test, P_A > 0.05), apart from CA versus CC (P_A = 0.020). The similar results were obtained in the subgroup analysis of Asian. In addition, we did not obtain the positive result in the meta‐analysis of rs2232365 (all P_A > 0.05). We also excluded the presence of large publication bias through Begg's test and Egger's test, and we confirmed the stability of data by sensitivity analysis. In summary, no significant association between rs3761548, rs2232365 polymorphisms of the FOXP3 gene, and an increased susceptibility to allergic rhinitis was identified based on the published data; however, this conclusion should be confirmed by more studies with increased sample sizes.     

ERAP1 variants are associated with ankylosing spondylitis in East Asian population: a new Chinese case–control study and meta‐analysis of published series

Endoplasmic reticulum aminopeptidase 1 (ERAP1) has been confirmed to be associated with ankylosing spondylitis (AS) in Caucasian. However, whether they are associated with AS in East Asian population remains unidentified. We investigated this relationship by a new Chinese case–control study and a meta‐analysis of published series. 368 cases and 460 controls were recruited in the Chinese case–control study. Genotyping was completed using the chip‐based matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry. Allelic associations were analysed using contingency tables. In the meta‐analysis, up to 2748 cases and 2774 controls from seven different studies and the new Chinese study were combined using Review Manager software version 5.1.1. Mantel–Haenszel or Inverse Variance test was used to calculate fixed or random‐effects pooled ORs. In the new Chinese study, strong association with AS was observed for marker rs10050860, rs27434 and rs1065407 at P value of <0.001. Moderate association was observed for rs30187 at P value of <0.01, while no association was observed for rs27044 (P = 0.37) and rs2287987 (P = 0.23). The meta‐analysis showed that rs27037 and rs30187 were strongly associated with AS (P < 0.00001). Significant association was also observed for rs27434 (P = 0.001). No association was shown for rs27044 (P = 0.70). We concluded that ERAP1 variants are associated with AS in East Asian population, indicating a common pathogenic mechanism for AS in East Asians and Caucasians.     

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.     

A family‐based association analysis and meta‐analysis of the reading disabilities candidate gene DYX1C1

Reading disabilities (RD) have a significant genetic basis and have shown linkage to multiple regions including chromosome 15q. Dyslexia susceptibility 1 candidate gene 1 (DYX1C1) on chromosome 15q21 was originally proposed as a candidate gene with two potentially functional polymorphisms at the ?3G/A and 1249G/T positions showing association with RD. However, subsequent studies have yielded mixed results. We performed a literature review and meta‐analysis of the ?3G/A and 1249G/T polymorphisms, including new unpublished data from two family‐based samples. Ten markers in DYX1C1 were genotyped in the two independently ascertained samples. Single marker and ?3G/A:1249G/T haplotype analyses were performed for RD in both samples, and quantitative trait analyses using standardized reading‐related measures was performed in one of the samples. For the meta‐analysis, we used a random‐effects model to summarize studies that tested for association between ?3G/A or 1249G/T and RD. No significant association was found between the DYX1C1 SNPs and RD or any of the reading‐related measures tested after correction for the number of tests performed. The previously reported risk haplotype (?3A:1249T) was not biased in transmission. A total of 9 and 10 study samples were included in the meta‐analysis of the ?3G/A and 1249G/T polymorphisms, respectively. Neither polymorphism reached statistical significance, but the heterogeneity for the 1249G/T polymorphism was high. The results of this study do not provide evidence for association between the putatively functional SNPs ?3G/A and 1249G/T and RD. © 2013 Wiley Periodicals, Inc.     

No association of genetic variants in BDNF with major depression: A meta‐ and gene‐based analysis

Major depressive disorder (MDD) is a complex psychiatric condition with strong genetic predisposition. The association of MDD with genetic polymorphisms, such as Val66Met (rs6265), in the brain derived neurotrophic factor (BDNF), have been reported in many studies and the results were conflicting. In this study, we performed a systematic literature search and conducted random‐effects meta‐analysis to evaluate genetic variants in BDNF with MDD. A gene‐based analysis was also conducted to investigate the cumulative effects of genetic polymorphisms in BDNF. A total of 28 studies from 26 published articles were included in our analysis. Meta‐analysis yielded an estimated odds ratio (OR) of 0.96 (95% CI: 0.89–1.05; P = 0.402) for Val66Met (rs6265), 0.83 (95% CI: 0.67–1.04; P = 0.103) for 11757C/G, 1.16 (95% CI: 0.74–1.82; P = 0.527) for 270T/C, 1.03 (95% CI: 0.18–5.75; P = 0.974) for 712A/G and 0.98 (95% CI: 0.85–1.14; P = 0.831) for rs988748. The gene‐based analysis indicated that BDNF is not associated with MDD (P > 0.21). Our updated meta‐ and novel gene‐based analyses provide no evidence of the association of BDNF with major depression. © 2012 Wiley Periodicals, Inc.     

Association of rs10490924 in ARMS2/HTRA1 with age‐related macular degeneration in the Pakistani population

Age‐related macular degeneration (AMD) is a disease of the elderly in which central vision is lost because of degenerative changes of the macula. The current study investigated the association of single‐nucleotide polymorphisms (SNPs) with AMD in the Pakistani population. Four SNPs were analyzed in this study: rs1061170 in the CFH, rs429608 near CFB, rs2230199 in the C3, and rs10490924 in ARMS2/HTRA1. This case‐control association study was conducted on 300 AMD patients (125 wet AMD and 175 dry AMD) and 200 unaffected age‐ and gender‐matched control individuals. The association of the SNP genotypes and allele frequency distributions were compared between patients and healthy controls, keeping age, gender, and smoking status as covariates. A significant genotype and variant allele association was found of rs10490924 in ARMS2/HTRA1 with wet AMD, while the SNPs in CFH, CFB, and C3 were not associated with AMD in the current Pakistani cohort. The lack of association of CFH, CFB, and C3 may be attributed to limited sample size. This study demonstrates that genetic causative factors of AMD differ among populations and supports the need for genetic association studies among cohorts from various populations to increase our global understanding of the disease pathogenesis.     

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.     

Potential Positive Association between Cytochrome P450 1A1 Gene Polymorphisms and Recurrent Pregnancy Loss: a Meta‐Analysis

In order to discover the potential genetic risks associated with recurrent pregnancy loss (RPL), this meta‐analysis was conducted to assess the association between CYP1A1 gene polymorphism and RPL. Studies were retrieved from the databases PubMed, Embase, HuGENet, and CNKI. Four models were then applied. Seven studies, including three datasets for the rs1048943 and five for the rs4646903 single‐nucleotide polymorphism (SNP), were included in this analysis, involving 613 cases and 398 controls for the rs1048943; and 864 cases and 842 controls for the rs4646903 SNP. After comprehensive analysis, we found that rs4646903 was significantly associated with RPL [recessive (OR = 1.72, 95%CI: 1.13–2.61); codominant (CC vs TT; OR = 1.74, 95%CI: 1.12–2.71), (CC vs CT; OR = 1.67, 95%CI: 1.07–2.62) and allele analysis (OR = 1.27, 95%CI: 1.07–1.50)]. In the following subgroup analysis, a positive association was also discovered among people of Asian descent, especially South Asians. However, there was no obvious association between rs1048943 and RPL. In summary, our results suggest that CYP1A1 gene polymorphism (particularly for rs4646903) might be associated with RPL risk, especially among South Asians. Further studies are required to confirm this association.