[Show abstract][Hide abstract] ABSTRACT: To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.
[Show abstract][Hide abstract] ABSTRACT: The Wellcome Trust Case Control Consortium 3 anorexia nervosa genome-wide association scan includes 2907 cases from 15 different populations of European origin genotyped on the Illumina 670K chip. We compared methods for identifying population stratification, and suggest list of markers that may help to counter this problem. It is usual to identify population structure in such studies using only common variants with minor allele frequency (MAF) >5%; we find that this may result in highly informative SNPs being discarded, and suggest that instead all SNPs with MAF >1% may be used. We established informative axes of variation identified via principal component analysis and highlight important features of the genetic structure of diverse European-descent populations, some studied for the first time at this scale. Finally, we investigated the substructure within each of these 15 populations and identified SNPs that help capture hidden stratification. This work can provide information regarding the designing and interpretation of association results in the International Consortia
European Journal of HumanGenetics 02/2014; · 4.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge–purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10−7) in SOX2OT and rs17030795 (P=5.84 × 10−6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10−6) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10−6) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10−6), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.
[Show abstract][Hide abstract] ABSTRACT: This study reports the appearance and characterization of multiple new polymorphic forms of indomethacin (IND). Considering the interest in amorphous suspensions for toxicology studies of poorly water soluble drugs, we sought to investigate the crystallization behaviour of amorphous IND in aqueous suspension. Specifically, the effect of pH and temperature on crystallization behaviour was studied. Quench cooled amorphous powder was added to buffered media at different pH values (1.2, 4.5, and 6.8) at 5 and 25°C. Both the solid and solution were analyzed at different time points up to 24 h. ATR-FTIR-spectroscopy (with principal component analysis) was used to study solid-phase transformations and UV-spectroscopy used to probe solution concentration. The crystallization onset time decreased and rate of crystallization increased with increasing pH and temperature. Diverse polymorphic forms were observed, with three new forms being identified; these were named ε, ζ and η. At 25°C, the amorphous form recrystallized directly to the α form, except at pH 6.8, where it initially converted briefly into the ε form. At 5°C, all three new polymorphic forms were observed sequentially in the order ε, ζ and then η, with the number of these forms observed increasing sequentially with decreasing pH. The three new forms exhibited distinct XPRD, DSC, and FTIR and Raman spectroscopy profiles. The solution concentration profiles suggest that the relative physical stabilities of the polymorphs at 5°C from lowest to highest is ε < ζ < η < α. The appearance of new polymorphs in this study, suggests that amorphous suspensions are worth considering when performing polymorphic screening studies.
[Show abstract][Hide abstract] ABSTRACT: Recent genome-wide association studies have identified genetic variants associated with blood pressure (BP). We investigated whether genetic risk scores (GRSs) constructed of these variants would predict incident cardiovascular disease (CVD) events. We genotyped 32 common single nucleotide polymorphisms in several Finnish cohorts, with up to 32 669 individuals after exclusion of prevalent CVD cases. The median follow-up was 9.8 years, during which 2295 incident CVD events occurred. We created GRSs separately for systolic BP and diastolic BP by multiplying the risk allele count of each single nucleotide polymorphism by the effect size estimated in published genome-wide association studies. We performed Cox regression analyses with and without adjustment for clinical factors, including BP at baseline in each cohort. The results were combined by inverse variance-weighted fixed-effects meta-analysis. The GRSs were strongly associated with systolic BP and diastolic BP, and baseline hypertension (all P<10(-62)). Hazard ratios comparing the highest quintiles of systolic BP and diastolic BP GRSs with the lowest quintiles after adjustment for age, age squared, and sex were 1.25 (1.07-1.46; P=0.006) and 1.23 (1.05-1.43; P=0.01), respectively, for incident coronary heart disease; 1.24 (1.01-1.53; P=0.04) and 1.35 (1.09-1.66; P=0.005), respectively, for incident stroke; and 1.23 (1.08-1.40; P=2×10(-6)) and 1.26 (1.11-1.44; P=5×10(-4)), respectively, for composite CVD. In conclusion, BP findings from genome-wide association studies are strongly replicated. GRSs comprising bona fide BP-single nucleotide polymorphisms predicted CVD risk, consistent with a lifelong effect on BP of these variants collectively.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: Low high-density lipoprotein cholesterol (HDL-C) is associated with cardiometabolic pathologies. In this study, we investigate the biological pathways and individual genes behind low HDL-C by integrating results from 3 high-throughput data sources: adipose tissue transcriptomics, HDL lipidomics, and dense marker genotypes from Finnish individuals with low or high HDL-C (n=450).Approach and Results-In the pathway analysis of genetic data, we demonstrate that genetic variants within inflammatory pathways were enriched among low HDL-C associated single-nucleotide polymorphisms, and the expression of these pathways upregulated in the adipose tissue of low HDL-C subjects. The lipidomic analysis highlighted the change in HDL particle quality toward putatively more inflammatory and less vasoprotective state in subjects with low HDL-C, as evidenced by their decreased antioxidative plasmalogen contents. We show that the focal point of these inflammatory pathways seems to be the human leukocyte antigen region with its low HDL-associated alleles also associating with more abundant local transcript levels in adipose tissue, increased plasma vascular cell adhesion molecule 1 levels, and decreased HDL particle plasmalogen contents, markers of adipose tissue inflammation, vascular inflammation, and HDL antioxidative potential, respectively. In a population-based look-up of the inflammatory pathway single-nucleotide polymorphisms in a large Finnish cohorts (n=11 211), no association of the human leukocyte antigen region was detected for HDL-C as quantitative trait, but with extreme HDL-C phenotypes, implying the presence of low or high HDL genes in addition to the population-genomewide association studies-identified HDL genes. CONCLUSIONS: Our study highlights the role of inflammation with a genetic component in subjects with low HDL-C and identifies novel cis-expression quantitative trait loci variants in human leukocyte antigen region to be associated with low HDL-C.
Arteriosclerosis Thrombosis and Vascular Biology 02/2013; · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To identify susceptibility loci for visceral leishmaniasis, we undertook genome-wide association studies in two populations: 989 cases and 1,089 controls from India and 357 cases in 308 Brazilian families (1,970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, and combined analysis across the three cohorts for rs9271858 at this locus showed P(combined) = 2.76 × 10(-17) and odds ratio (OR) = 1.41, 95% confidence interval (CI) = 1.30-1.52. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion, the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species.
[Show abstract][Hide abstract] ABSTRACT: To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association analysis on monozygotic twin-pairs offers a route to discovery of gene-environment interactions through testing for variability loci associated with sensitivity to individual environment/lifestyle. We present a genome-wide scan of loci associated with intra-pair differences in serum lipid and apolipoprotein levels. We report data for 1,720 monozygotic female twin-pairs from GenomEUtwin project with 2.5 million SNPs, imputed or genotyped, and measured serum lipid fractions for both twins. We found one locus associated with intra-pair differences in high-density lipoprotein cholesterol, rs2483058 in an intron of SRGAP2, where twins carrying the C allele are more sensitive to environmental factors (P = 3.98 × 10-8). We followed up the association in further genotyped monozygotic twins (N = 1,261), which showed a moderate association for the variant (P = 0.200, same direction of an effect). In addition, we report a new association on the level of apolipoprotein A-II (P = 4.03 × 10-8).
Twin Research and Human Genetics 10/2012; · 1.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising ,852 UK cases and 5,72 UK controls in the discovery stage and 5,986 cases and 2,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p2, rs9257809 (P combined = 4.09 × 0 −9 ; odds ratio (OR) = .2, 95% confidence interval (CI) =.3–.28), within the major histocompatibility complex locus, and chromosome 6q24, rs9936833 (P combined = 2.74 × 0 −0 ; OR = .4, 95% CI = .0–.9), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus. Barrett's esophagus is one of the most common premalignant lesions in the western world. It affects over 2% of the adult population and, unlike bowel polyps, lacks any proven effective therapy 1 . In the major-ity of cases, Barrett's esophagus is associated with chronic gastro-esophageal reflux disease (GERD), including esophagitis 2,3 . Over 80% of affected individuals have a hiatus hernia in the lower esophagus that facilitates the reflux of acid and bile into the esophagus 4 . The measured annual risk of EAC in individuals with Barrett's esophagus varies widely but is approximately 0.4–1% (refs. 5–7). Notably, the incidence of EAC has been rising by 3% each year for the last 30 years; it is now the fifth most common cancer in the UK 8 . Despite modern multimodality therapy, the prog-nosis for EAC remains poor, with a 9–15% 5-year survival rate 9,10 . The etiology of Barrett's esophagus is not well characterized. Environmental factors, such as diet, are weakly associated with GERD, Barrett's esophagus and EAC, and obesity is a known risk factor for all three conditions 11 . There is also evidence implicating genetic factors: relative risks are increased by 2-to 4-fold for GERD, Barrett's esophagus and EAC when one first-degree relative is affected 12–17 . A segregation analysis of 881 pedigrees of familial Barrett's esophagus supports an incompletely dominant inheritance model with a polygenic component 18 . Extensive candidate gene and linkage searches have to date been unsuccessful in identifying genetic variants that are associated with risk of Barrett's esophagus 19 . As part of the Wellcome Trust Case Control Consortium 2 (WTCCC2) study of 15 common disorders and traits, we present the results of the first genome-wide association study of Barrett's esophagus susceptibility. Using a discovery cohort from the UK (with case samples from the Aspirin and Esomeprazole Chemoprevention Trial of Cancer in Barrett's esophagus (AspECT)) 20 and five repli-cation cohorts (including case samples from CHemoprevention Of Premalignant Intestinal Neoplasia (ChOPIN) and Esophageal Adenocarcinoma GenEtics Consortium (EAGLE) studies 9,20), we identified two variants associated with Barrett's esophagus, each with combined evidence at P < 5 × 10 −8 . The analysis workflow is outlined in Supplementary Figure 1, and characteristics of the case and con-trol samples that were included can be found in the Online Methods and Supplementary Table 1. For the discovery analysis, cases with histologically confirmed Barrett's esophagus (Online Methods) were recruited from sites across the UK (Supplementary Table 2). Population controls were taken from the WTCCC2 common set of 1958 Birth Cohort (58C) and National Blood Service (UKBS) samples as previously described 21 .
[Show abstract][Hide abstract] ABSTRACT: Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (P(combined) = 4.09 × 10(-9); odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (P(combined) = 2.74 × 10(-10); OR = 1.14, 95% CI = 1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.
[Show abstract][Hide abstract] ABSTRACT: To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.
[Show abstract][Hide abstract] ABSTRACT: Some genetic loci may affect susceptibility to multiple immune system-related diseases. In the current study, we investigated whether the known susceptibility loci for celiac disease (CelD) also associate with Crohn's disease (CD) and/or ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), in Finnish patients. A total of 45 genetic markers were genotyped in a Finnish data set comprising 699 IBD patients and 2482 controls. Single-marker association with IBD and its subphenotypes was tested. A meta-analysis with a Swedish UC data set was also performed. A total of 12 single-nucleotide polymorphisms associated with CD and/or UC (P<0.05). In the subphenotype analysis, rs6974491-ELMO1 (P=0.0002, odds ratio (OR): 2.20) and rs2298428-UBE2L3 (P=5.44 × 10(-5), OR: 2.59) associated with pediatric UC and CD, respectively. In the meta-analysis, rs4819388-ICOSLG (P=0.00042, OR: 0.79) associated with UC. In the subphenotype meta-analysis, rs1738074-TAGAP (P=7.40 × 10(-5), OR: 0.61), rs6974491-ELMO1 (P=0.00052, OR: 1.73) and rs4819388-ICOSLG (P=0.00019, OR: 0.75) associated with familial UC, pediatric UC and sporadic UC, respectively. Multiple CelD risk loci also confer susceptibility for CD and/or UC in the Finnish and Swedish populations. Certain genetic risk variants may furthermore predispose an individual for developing a particular disease phenotype.
Genes and immunity 05/2012; 13(6):474-80. · 4.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
[Show abstract][Hide abstract] ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder with a significant public-health impact. Previously, we described a candidate gene study in a population-based birth cohort that demonstrated an association with ADHD-affected males and the dopamine receptor D2 (DRD2). The current study evaluates potential associations of dopamine receptor genes and Cloninger temperament traits within this same sample. Participants with stringent lifetime ADHD diagnoses were ascertained systematically from the genetically isolated Northern Finland 1986 Birth Cohort (n=9432), resulting in 178 cases and 157 controls. Markers in all known dopamine receptor genes were genotyped. We report an association of DRD2 with low Persistence in females (rs1079727 P=0.02, rs1124491 P=0.02, rs1800497 P=0.03). The associated DRD2 minor allelic haplotype (CAA, P=0.03) is the same haplotype we previously associated with ADHD in males in this birth cohort. The current study further supports previous results on the role of DRD2 in individuals with ADHD. Investigations suggest that DRD2 may have an impact on both males and females, but the particular outcome appears sex-specific, manifesting as ADHD in males and low Persistence in females. Furthermore, these findings suggest that the putative role of low Persistence as an endophenotype for ADHD deserves further investigation.
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association (GWA) studies have identified several susceptibility loci for metabolic syndrome (MetS) component traits, but have had variable success in identifying susceptibility loci to the syndrome as an entity. We conducted a GWA study on MetS and its component traits in 4 Finnish cohorts consisting of 2637 MetS cases and 7927 controls, both free of diabetes, and followed the top loci in an independent sample with transcriptome and nuclear magnetic resonance-based metabonomics data. Furthermore, we tested for loci associated with multiple MetS component traits using factor analysis, and built a genetic risk score for MetS.
A previously known lipid locus, APOA1/C3/A4/A5 gene cluster region (SNP rs964184), was associated with MetS in all 4 study samples (P=7.23×10(-9) in meta-analysis). The association was further supported by serum metabolite analysis, where rs964184 was associated with various very low density lipoprotein, triglyceride, and high-density lipoprotein metabolites (P=0.024-1.88×10(-5)). Twenty-two previously identified susceptibility loci for individual MetS component traits were replicated in our GWA and factor analysis. Most of these were associated with lipid phenotypes, and none with 2 or more uncorrelated MetS components. A genetic risk score, calculated as the number of risk alleles in loci associated with individual MetS traits, was strongly associated with MetS status.
Our findings suggest that genes from lipid metabolism pathways have the key role in the genetic background of MetS. We found little evidence for pleiotropy linking dyslipidemia and obesity to the other MetS component traits, such as hypertension and glucose intolerance.
[Show abstract][Hide abstract] ABSTRACT: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.