Genome-wide Significant Association Research Articles

A Genome-Wide Association Study Reveals New Genes in a Molecular Network Associated with Alcohol Dependence and Related Clinical Measures

Background: Alcohol dependence (AD) is a cluster of clinical phenomena that develop after repeated alcohol use. At least 50% of factors predisposing to AD are genetic and women affected with this disorder present with more psychiatric comorbidities, probably indicating different genetic factors involved. We aimed to run a genome-wide association study (GWAS) followed by a bioinformatic functional annotation of associated genomic regions in a cohort of patients with AD and eight additional clinical measures. Methods: Chi-square tests and the signal localization approach were used for the genome-wide screening of associations with AD. Likelihood ratio tests were used to evaluate associations with the additional clinical measures. Regulatory sequences in the associated linkage disequilibrium blocks were retrieved from bioinformatic databases. The resulting list of regulated genes was analyzed for possible interactions. Results: A genome-wide significant association of rs220677 with AD (p-value = 1.33×10-8) was discovered in female patients. Associations with six other single nucleotide polymorphisms listed in previous GWAS of psychiatric and addiction traits were differently replicated in female and male patients. The bioinformatic analysis showed that regulatory elements in the seven associated linkage disequilibrium blocks define the expression of 78 protein-coding genes. Nearly 68% of these and of 120 other previously published coding genes associated with alcohol phenotypes directly interact in a single network (i.e. without additional interactors added by the software). Conclusions: Results of this study suggest that molecular pathways implicated in the pathogenesis of AD are the same in both sexes, but different genes play more prominent roles in men and women. The discovered gene network may contain clues to the understanding of the pathogenesis and to the discovery of new treatment options of AD.

Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study

The genetic basis of variation in the progression of primary tauopathies has not been determined. We aimed to identify genetic determinants of survival in progressive supranuclear palsy (PSP). In stage one of this two stage genome-wide association study (GWAS), we included individuals with PSP, diagnosed according to pathological and clinical criteria, from two separate cohorts: the 2011 PSP GWAS cohort, from brain banks based at the Mayo Clinic (Jacksonville, FL, USA) and in Munich (Germany), and the University College London PSP cohort, from brain banks and the PROSPECT study, a UK-wide longitudinal study of patients with atypical parkinsonian syndromes. Individuals were included if they had clinical data available on sex, age at motor symptom onset, disease duration (from motor symptom onset to death or to the date of censoring, Dec 1, 2019, if individuals were alive), and PSP phenotype (with reference to the 2017 Movement Disorder Society criteria). Genotype data were used to do a survival GWAS using a Cox proportional hazards model. In stage two, data from additional individuals from the Mayo Clinic brain bank, which were obtained after the 2011 PSP GWAS, were used for a pooled analysis. We assessed the expression quantitative trait loci (eQTL) profile of variants that passed genome-wide significance in our GWAS using the Functional Mapping and Annotation of GWAS platform, and did colocalisation analyses using the eQTLGen and PsychENCODE datasets. Data were collected and analysed between Aug 1, 2016, and Feb 1, 2020. Data were available for 1001 individuals of white European ancestry with PSP in stage one. We found a genome-wide significant association with survival at chromosome 12 (lead single nucleotide polymorphism rs2242367, p=7·5 × 10-10, hazard ratio 1·42 [95% CI 1·22-1·67]). rs2242367 was associated with survival in the individuals added in stage two (n=238; p=0·049, 1·22 [1·00-1·48]) and in the pooled analysis of both stages (n=1239; p=1·3 × 10-10, 1·37 [1·25-1·51]). An eQTL database screen revealed that rs2242367 is associated with increased expression of LRRK2 and two long intergenic non-coding RNAs (lncRNAs), LINC02555 and AC079630.4, in whole blood. Although we did not detect a colocalisation signal for LRRK2, analysis of the PSP survival signal and eQTLs for LINC02555 in the eQTLGen blood dataset revealed a posterior probability of hypothesis 4 of 0·77, suggesting colocalisation due to a single shared causal variant. Genetic variation at the LRRK2 locus was associated with survival in PSP. The mechanism of this association might be through a lncRNA-regulated effect on LRRK2 expression because LINC02555 has previously been shown to regulate LRRK2 expression. LRRK2 has been associated with sporadic and familial forms of Parkinson's disease, and our finding suggests a genetic overlap with PSP. Further functional studies will be important to assess the potential of LRRK2 modulation as a disease-modifying therapy for PSP and related tauopathies. PSP Association, CBD Solutions, Medical Research Council (UK).

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P=1.65×10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P=2.3×10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P=3.98×10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P=4.99×10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.

The influence of adult hip shape genetic variants on adolescent hip shape: Findings from a population-based DXA study.

ObjectiveHip shape is a well-recognized risk factor for hip osteoarthritis (OA) and hip fracture. We aimed to investigate whether the genetic variants known to be associated with adult hip shape were also associated with adolescent hip shape.MethodsHip DXA scans, obtained in offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) at two time points (mean ages 13.8 and 17.8 years), were used to quantify hip morphology using a 53-point Statistical Shape Model (SSM). Principal component analysis was used to generate hip shape modes (HSMs). Genetic variants which had previously shown genome-wide significant association with specific HSMs in adults were tested for association with the same HSMs in adolescents (at each timepoint separately) using SNPTEST v2.ResultsComplete genotypic and phenotypic data were available for 3550 and 3175 individuals at 14 and 18 years, respectively. The strongest evidence for association with adolescent hip shape was for a variant located near SOX9 (rs2158915) with consistent effects across both time points for HSM1 (age 14: beta −0.05, p = 9.9 × 10−8; age 18: −0.05, p = 3.3 × 10−6) and HSM5 (age 14: beta −0.07, p = 1.6 × 10−4; age 18: −0.1, p = 2.7 × 10−6). There was also strong evidence of association between rs10743612 (near PTHLH) and HSM1 (age 14: 0.05, p = 1.1 × 10−5; age 18: 0.04, p = 0.003) and between rs6537291 (near HHIP) and HSM2 (age 14: −0.06, p = 0.001; age 18: −0.07, p = 0.001) across both time points. The genes with the strongest associations with hip shape in adolescents, (SOX9, PTHLH and HHIP) are known to be involved in endochondral bone formation. HSM1 indicates narrower aspect ratio of the upper femur, whereas both HSM2 and HSM5 reflect variation in the femoral head size and femoral neck width, features previously found to be related to the risk of OA in later life. The SOX9 locus has previously been found to associate with increased risk of hip fracture.ConclusionIn conclusion, variants implicated in endochondral bone formation appear to consistently influence hip shape between adolescence and adulthood, including those aspects related to risk of hip OA and/or fracture in later life.

Evaluating human autosomal loci for sexually antagonistic viability selection in two large biobanks.

Sex and sexual differentiation are pervasive across the tree of life. Because females and males often have substantially different functional requirements, we expect selection to differ between the sexes. Recent studies in diverse species, including humans, suggest that sexually antagonistic viability selection creates allele frequency differences between the sexes at many different loci. However, theory and population-level simulations indicate that sex-specific differences in viability would need to be very large to produce and maintain reported levels of between-sex allelic differentiation. We address this contradiction between theoretical predictions and empirical observations by evaluating evidence for sexually antagonistic viability selection on autosomal loci in humans using the largest cohort to date (UK Biobank, n = 487,999) along with a second large, independent cohort (BioVU, n = 93,864). We performed association tests between genetically ascertained sex and autosomal loci. Although we found dozens of genome-wide significant associations, none replicated across cohorts. Moreover, closer inspection revealed that all associations are likely due to cross-hybridization with sex chromosome regions during genotyping. We report loci with potential for mis-hybridization found on commonly used genotyping platforms that should be carefully considered in future genetic studies of sex-specific differences. Despite being well powered to detect allele frequency differences of up to 0.8% between the sexes, we do not detect clear evidence for this signature of sexually antagonistic viability selection on autosomal variation. These findings suggest a lack of strong ongoing sexually antagonistic viability selection acting on single locus autosomal variation in humans.

The genetic architecture of sporadic and multiple consecutive miscarriage

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10−8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10−8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10−9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10−8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.

Genome-Wide Association Analysis Identified BMPR1A as a Novel Candidate Gene Affecting the Number of Thoracic Vertebrae in a Large White × Minzhu Intercross Pig Population.

Simple SummaryThe number of thoracic vertebrae (NTV) and number of vertebrae (NV) varies among pig breeds with a high correlation of about 0.8. It is important to discover variants associated with the NTV by considering the effect of the NV in pig. The results suggest that regulation variants on SSC7 might play crucial roles in the NTV and the FOS on SSC7 should be further studied as a critical candidate gene. In addition, BMPR1A was identified as a novel candidate gene affecting the NTV in pigs.The number of vertebrae (NV), especially the number of thoracic vertebrae (NTV), varies among pig breeds. The NTV is controlled by vertebral segmentation and the number of somites during embryonic development. Although there is a high correlation between the NTV and NV, studies on a fixed NV have mainly considered the absolute numbers of thoracic vertebrae instead of vertebral segmentation. Therefore, this study aimed to discover variants associated with the NTV by considering the effect of the NV in pigs. The NTV and NV of 542 F2 individuals from a Large White × Minzhu pig crossbreed were recorded. All animals were genotyped for VRTN g.19034 A > C, LTBP2 c.4481A > C, and 37 missense or splice variants previously reported in a 951-kb interval on SSC7 and 147 single nucleotide polymorphisms (SNPs) on SSC14. To identify NTV-associated SNPs, we firstly performed a genome-wide association study (GWAS) using the Q + K (population structure + kinship matrix) model in TASSEL. With the NV as a covariate, the obtained data were used to identify the SNPs with the most significant genome-wide association with the NTV by performing a GWAS on a PorcineSNP60K Genotyping BeadChip. Finally, a conditional GWAS was performed by fixing this SNP. The GWAS showed that 31 SNPs on SSC7 have significant genome-wide associations with the NTV. No missense or splice variants were found to be associated with the NTV significantly. A linkage disequilibrium analysis suggested the existence of quantitative trait loci (QTL) in a 479-Kb region on SSC7, which contained a critical candidate gene FOS for the NTV in pigs. Subsequently, a conditional GWAS was performed by fixing M1GA0010658, the most significant of these SNPs. Two SNPs in BMPR1A were found to have significant genome-wide associations and a significant dominant effect. The leading SNP, S14_87859370, accounted for 3.86% of the phenotypic variance. Our study uncovered that regulation variants in FOS on SSC7 and in BMPR1A on SSC14 might play important roles in controlling the NTV, and thus these genetic factors may be harnessed for increasing the NTV in pigs.

Genome-Wide Association Study Identifies Genomic Loci of Sex Determination and Gonadosomatic Index Traits in Large Yellow Croaker (Larimichthys crocea).

Larimichthys crocea is one of the traditional marine culture fishes in China, widely distributed in South China Sea, East Sea, and southern Yellow Sea. Sex dimorphism is evident in this species that females present a substantial growth strength than males, suggesting breeding females could obtain more economic benefits in L. crocea aquaculture industry. With the continuous expansion of aquaculture industry, both identifying sex-associated genome region and understanding the genetic basis underlying gonad differentiation and development matter to not only sex control aquaculture but also breeding industry. Thus, genome-wide association analysis (GWAS) of sex determination was conducted with a random breeding population of 905 individuals (including 463 females and 442 males) by ddRAD sequencing. For sex determination, 21 significant single nucleotide polymorphisms (SNPs) in chromosome (Chr) 22 were identified. Surrounding these SNPs, we founded 14 candidate genes, including dmrt1, dmrt3, and piwil2, fam102a, and odf2. The sex-associated region was narrowed down further to 2.4Mb on Chr22 through Fst scanning and insertion-deletion (InDel) analysis. Besides, 3 SNPs in the supposed sex-determining region on Chr22 were identified as highly associated with gonad differentiation through GWAS on gonadosomatic index (GSI) in 350 males and 231 females. Because of the significant difference of GSI between females and males of L. crocea, GWAS on GSI of different genders was also conducted independently. Finally, we identified a SNP in Chr18 showing genome-wide significant association with male GSI (MGSI) and three genes axl, cyp2a10, and cyp2g1 involved in the gonadal development regulation process of aromatase. Overall, this study explored the genetic basis of sex determination mechanism and provided novel insights into gonad differentiation and development, offering solid genetic support for sex control breeding, marker-assisted selection, and marine resources conservation.

Rapid response to the alpha-1 adrenergic agent phenylephrine in the perioperative period is impacted by genomics and ancestry

The emergence of genomic data in biobanks and health systems offers new ways to derive medically important phenotypes, including acute phenotypes occurring during inpatient clinical care. Here we study the genetic underpinnings of the rapid response to phenylephrine, an α1-adrenergic receptor agonist commonly used to treat hypotension during anesthesia and surgery. We quantified this response by extracting blood pressure (BP) measurements 5 min before and after the administration of phenylephrine. Based on this derived phenotype, we show that systematic differences exist between self-reported ancestry groups: European-Americans (EA; n = 1387) have a significantly higher systolic response to phenylephrine than African-Americans (AA; n = 1217) and Hispanic/Latinos (HA; n = 1713) (31.3% increase, p value < 6e−08 and 22.9% increase, p value < 5e−05 respectively), after adjusting for genetic ancestry, demographics, and relevant clinical covariates. We performed a genome-wide association study to investigate genetic factors underlying individual differences in this derived phenotype. We discovered genome-wide significant association signals in loci and genes previously associated with BP measured in ambulatory settings, and a general enrichment of association in these genes. Finally, we discovered two low frequency variants, present at ~1% in EAs and AAs, respectively, where patients carrying one copy of these variants show no phenylephrine response. This work demonstrates our ability to derive a quantitative phenotype suited for comparative statistics and genome-wide association studies from dense clinical and physiological measures captured for managing patients during surgery. We identify genetic variants underlying non response to phenylephrine, with implications for preemptive pharmacogenomic screening to improve safety during surgery.

Little Evidence of Modified Genetic Effect of rs16969968 on Heavy Smoking Based on Age of Onset of Smoking.

Tobacco smoking is the leading cause of preventable death globally. Smoking quantity, measured in cigarettes per day, is influenced both by the age of onset of regular smoking (AOS) and by genetic factors, including a strong effect of the nonsynonymous single-nucleotide polymorphism rs16969968. A previous study by Hartz et al. reported an interaction between these two factors, whereby rs16969968 risk allele carriers who started smoking earlier showed increased risk for heavy smoking compared with those who started later. This finding has yet to be replicated in a large, independent sample. We performed a preregistered, direct replication attempt of the rs16969968 × AOS interaction on smoking quantity in 128 383 unrelated individuals from the UK Biobank, meta-analyzed across ancestry groups. We fit statistical association models mirroring the original publication as well as formal interaction tests on multiple phenotypic and analytical scales. We replicated the main effects of rs16969968 and AOS on cigarettes per day but failed to replicate the interaction using previous methods. Nominal significance of the rs16969968 × AOS interaction term depended strongly on the scale of analysis and the particular phenotype, as did associations stratified by early/late AOS. No interaction tests passed genome-wide correction (α = 5e-8), and all estimated interaction effect sizes were much smaller in magnitude than previous estimates. We failed to replicate the strong rs16969968 × AOS interaction effect previously reported. If such gene-moderator interactions influence complex traits, they likely depend on scale of measurement, and current biobanks lack the power to detect significant genome-wide associations given the minute effect sizes expected. We failed to replicate the strong rs16969968 × AOS interaction effect on smoking quantity previously reported. If such gene-moderator interactions influence complex traits, current biobanks lack the power to detect significant genome-wide associations given the minute effect sizes expected. Furthermore, many potential interaction effects are likely to depend on the scale of measurement employed.

Genome-Wide Association Study Identifies Variation in ABO As Risk Factor for Platelet Reactivity in Heparin-Induced Thrombocytopenia

Background: Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect of heparin treatment resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. Genome-wide association studies (GWAS) have the potential to identify genetic risk factors and generate insights into biological mechanisms of adverse drug reactions. However, published HIT GWAS are underpowered and do not include confirmation of HIT using functional assays. We aimed to identify genetic associations with HIT using a GWAS approach in two European ancestry populations tested for functional assay and PF4/heparin antibody levels. Methods: We performed a GWAS with positive functional assay as the outcome in a large discovery cohort of patients, including heparin-induced platelet aggregation (HIPA) positive cases (n=1243), antibody positive but functional assay negative controls (n=1091), and antibody negative controls (n=1718). Logistic regressions were adjusted for age, gender, and first two principal components. Significant associations from the discovery cohort (alpha=5.00x10-8) were then investigated in a replication cohort of serotonin-release assay (SRA)-confirmed HIT cases (n=173), antibody positive controls (n=125), and antibody negative controls (n=488). All patients were genotyped with the HumanOmniExpressExome BeadChip, including 9,065,510 variants after imputation and quality control. Genes near significantly associated loci were resequenced. Results: In the discovery cohort, a genome-wide significant association was observed between common variation in the ABO gene and HIPA positive status (rs505922 odds ratio 0.738 [0.668-0.816], p=2.813x10-9). This variant was also significantly associated with SRA-confirmed HIT in the replication cohort (odds ratio 0.392 [0.172-0.891], p=0.025). Meta-analysis indicated strong association of ABO variation with positive functional assay (Figure 1). Sequencing and fine-mapping of the ABO locus indicated this effect was driven by ABO blood groups, with the O blood group being a risk factor for HIT (odds ratio 1.42 [1.25-1.61], p=6.11x10-8). Conclusions: We identify common variation in ABO as a risk factor for platelet reactivity and HIT. Strong association of ABO variation may have important implications for prediction and understanding of HIT pathogenesis. Figure 1 Disclosures No relevant conflicts of interest to declare.

A genome-wide association study identifies novel genetic loci associated with pulmonary embolism

Abstract Background Pulmonary embolism (PE) is a life-threatening cardiovascular condition. Studies showed that PE patients were associated with disorders of lipid metabolism and had higher triglyceride and lower HDL-C levels compared with healthy. We conducted the genome-wide association study to identify novel loci contributing to PE. Methods We conducted a large-scale GWAS of PE in 5,466 PE cases and 461,219 controls of European ancestry from the UK Biobank (466,685 participants total). We used genome-wide summary statistics to test for enrichment of functional annotations using ENRICHR. Example pathways included in Enrichr for testing include membership of genes in pathway databases such as the Kyoto Encyclopedia of Genes and Genomes (KEGG), Wikipathway, PANTHER, BioCarta or NCI-Nature pathways. We analyzed the pathways using combined score and p-values which were well validated by comparing to several methods. For pathway analyses, we considered a nominal P-value threshold of 0.05. Results We identified genome-wide significant genetic associations in 63 independent genetic loci for PE (P&amp;lt;5.0x10–7). Our findings for top pathways highlight that lipid metabolism (LIPC, LCAT, NPC2), caffeine metabolism (NAT2), and sudden cardiac death (ABCG8) related genetic loci play an important role in PE alongside genes already associated with coagulation-thrombosis pathway (VWF, THPO, PTPN11, INPP5D, UROS, HMBS) (all p-values p-values &amp;lt;0.05). Conclusion Our findings uncovered unexpected novel factors of PE etiology, suggesting novel mechanistic concepts of PE pathophysiology. Funding Acknowledgement Type of funding source: None

GENECHOC study: genetic markers of arrhythmic risk in heart failure

Abstract Background Ventricular arrhythmic events are responsible for 50% of death in heart failure but no reliable predictive marker is known to discriminate patients at risk of fatal arrhythmia. Interestingly, familial predisposition has been reported suggesting a role of genetic factors. Purpose Identify genetic markers increasing the arrhythmic risk in heart failure population. Method We prospectively included heart failure patients with left ventricular ejection fraction (LVEF) under 35% and a cardioverter defibrillator in primary prevention in 22 French centres between 2009 and 2017. Patients were followed for 72 months and divided into two groups: cases with an arrhythmic event during follow-up and controls. A Genome Wide Association Study (GWAS) was done. Single Nucleotide Polymorphisms (SNPs) genotyping was performed on Affymetrix Axiom Precision Medicine Research Array plates. To complement the directly genotyped SNPs we performed large-scale imputation based on the Haplotype Reference Consortium European ancestry panel leading to a dataset of 7,5 million of SNPs. Results 332 cases and 567 controls were included (86% men, mean age at implantation 52±11 years). 78% of patients had ischaemic cardiopathy, 20% had dilated cardiomyopathy. Mean LVEF was 27±5%. No statistical difference was found between cases and controls on clinical parameters, biological results, electrocardiographic measures. No locus shows genome-wide significant association (p&amp;lt;5.10–8) on the GWAS analysis. However, 16 signals with a p-value between 5.10–8 and 5.10–5 were investigated. eQTL and chromatin conformation point to 35 genes with cardiac expression previously associated with heart failure, cardiomyopathies, cardiogenesis, arrhythmias and inflammation. Variants identified point to regulatory regions of the genome and may then propose a molecular mechanism predisposing patients to arrhythmias. Conclusion No locus raises genome-wide significance, but several signals with a nominal p-value point to relevant genes and pathways. Replication of the GWAS is ongoing on a cohort of 156 new patients with a less severe cardiopathy implanted with a cardioverter defibrillator in secondary prevention. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Nantes University Hospital

Identification of Genetic Variants for Female Obesity and Evaluation of the Causal Role of Genetically Defined Obesity in Polycystic Ovarian Syndrome.

PurposeObservational studies have demonstrated an increased risk of polycystic ovarian syndrome (PCOS) in obese women. This study aimed to identify genetic variants influencing obesity in females and to evaluate the causal association between genetically defined obesity and PCOS in Korean women.MethodsTwo-stage GWAS was conducted to identify genetic variants influencing obesity traits (such as body mass index [BMI], waist–hip ratio [WHR], and waist circumference [WC]) in Korean women. Two-sample Mendelian randomization (MR) analysis was employed to evaluate the causal effect of variants as genetic instruments for female obesity on PCOS.ResultsMeta-analysis of 9953 females combining discovery (N = 4658) and replication (N = 5295) stages detected four (rs11162584, rs6760543, rs828104, rs56137030), six (rs139702234, rs2341967, rs73059848, rs5020945, rs550532151, rs61971548), and two genetic variants (rs7722169, rs7206790) suggesting a highly significant association (P < 1×10−6) with BMI, WHR, and WC, respectively. Of these, an intron variant rs56137030 in FTO achieved genome-wide significant association (P = 3.39×10−8) with BMI in females. Using variants for female obesity, their effect on PCOS in 946 cases and 976 controls was evaluated by MR analysis. MR results indicated no significant association between genetically defined obesity and PCOS in Korean women.ConclusionThis study, for the first time, revealed genetic variants for female obesity in the Korean population and reported no causal association between genetically defined obesity and PCOS in Korean women.

Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations.

Agranulocytosis is a rare yet severe idiosyncratic adverse drug reaction to metamizole, an analgesic widely used in countries such as Switzerland and Germany. Notably, an underlying mechanism has not yet been fully elucidated and no predictive factors are known to identify at-risk patients. With the aim to identify genetic susceptibility variants to metamizole-induced agranulocytosis (MIA) and neutropenia (MIN), we conducted a retrospective multi-center collaboration including cases and controls from three European populations. Association analyses were performed using genome-wide genotyping data from a Swiss cohort (45 cases, 191 controls) followed by replication in two independent European cohorts (41 cases, 273 controls) and a joint discovery meta-analysis. No genome-wide significant associations (p < 1 × 10−7) were observed in the Swiss cohort or in the joint meta-analysis, and no candidate genes suggesting an immune-mediated mechanism were identified. In the joint meta-analysis of MIA cases across all cohorts, two candidate loci on chromosome 9 were identified, rs55898176 (OR = 4.01, 95%CI: 2.41–6.68, p = 1.01 × 10−7) and rs4427239 (OR = 5.47, 95%CI: 2.81–10.65, p = 5.75 × 10−7), of which the latter is located in the SVEP1 gene previously implicated in hematopoiesis. This first genome-wide association study for MIA identified suggestive associations with biological plausibility that may be used as a stepping-stone for post-GWAS analyses to gain further insight into the mechanism underlying MIA.

Inclusion of endophenotypes in a standard GWAS facilitate a detailed mechanistic understanding of genetic elements that control blood lipid levels

Dyslipidemia is the primary cause of cardiovascular disease, which is a serious human health problem in large parts of the world. Therefore, it is important to understand the genetic and molecular mechanisms that regulate blood levels of cholesterol and other lipids. Discovery of genetic elements in the regulatory machinery is often based on genome wide associations studies (GWAS) focused on end-point phenotypes such as total cholesterol level or a disease diagnosis. In the present study, we add endophenotypes, such as serum levels of intermediate metabolites in the cholesterol synthesis pathways, to a GWAS analysis and use the pig as an animal model. We do this to increase statistical power and to facilitate biological interpretation of results. Although the study population was limited to ~ 300 individuals, we identify two genome-wide significant associations and ten suggestive associations. Furthermore, we identify 28 tentative associations to loci previously associated with blood lipids or dyslipidemia associated diseases. The associations with endophenotypes may inspire future studies that can dissect the biological mechanisms underlying these previously identified associations and add a new level of understanding to previously identified associations.

A Polygenic Score for Type 2 Diabetes Risk Is Associated With Both the Acute and Sustained Response to Sulfonylureas.

There is a limited understanding of how genetic loci associated with glycemic traits and type 2 diabetes (T2D) influence the response to antidiabetic medications. Polygenic scores provide increasing power to detect patterns of disease predisposition that might benefit from a targeted pharmacologic intervention. In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), we constructed weighted polygenic scores using known genome-wide significant associations for T2D, fasting glucose, and fasting insulin, comprising 65, 43, and 13 single nucleotide polymorphisms, respectively. Multiple linear regression tested for associations between scores and glycemic traits as well as pharmacodynamic end points, adjusting for age, sex, race, and BMI. A higher T2D score was nominally associated with a shorter time to insulin peak, greater glucose area over the curve, shorter time to glucose trough, and steeper slope to glucose trough after glipizide. In replication, a higher T2D score was associated with a greater 1-year hemoglobin A1c reduction to sulfonylureas in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study (P = 0.02). Our findings suggest that individuals with a higher genetic burden for T2D experience a greater acute and sustained response to sulfonylureas.

Genetic variation in GC and CYP2R1 affects 25-hydroxyvitamin D concentration and skeletal parameters: A genome-wide association study in 24-month-old Finnish children

Vitamin D is important for normal skeletal homeostasis, especially in growing children. There are no previous genome-wide association (GWA) studies exploring genetic factors that influence vitamin D metabolism in early childhood. We performed a GWA study on serum 25-hydroxyvitamin D (25(OH)D) and response to supplementation in 761 healthy term-born Finnish 24-month-old children, who participated in a randomized clinical trial comparing effects of 10 μg and 30 μg of daily vitamin D supplementation from age 2 weeks to 24 months. Using the Illumina Infinium Global Screening Array, which has been optimized for imputation, a total of 686085 markers were genotyped across the genome. Serum 25(OH)D was measured at the end of the intervention at 24 months of age. Skeletal parameters reflecting bone strength were determined at the distal tibia at 24 months using peripheral quantitative computed tomography (pQCT) (data available for 648 children). For 25(OH)D, two strong GWA signals were identified, localizing to GC (Vitamin D binding protein) and CYP2R1 (Vitamin D 25-hydroxylase) genes. The GWA locus comprising the GC gene also associated with response to supplementation. Further evidence for the importance of these two genes was obtained by comparing association signals to gene expression data from the Genotype-Tissue Expression project and performing colocalization analyses. Through the identification of haplotypes associated with low or high 25(OH)D concentrations we used a Mendelian randomization approach to show that haplotypes associating with low 25(OH)D were also associated with low pQCT parameters in the 24-month-old children. In this first GWA study on 25(OH)D in this age group we show that already at the age of 24 months genetic variation influences 25(OH)D concentrations and determines response to supplementation, with genome-wide significant associations with GC and CYP2R1. Also, the dual association between haplotypes, 25(OH)D and pQCT parameters gives support for vertical pleiotropy mediated by 25(OH)D.

A genome-wide association analysis for body, udder, and leg conformation traits recorded in Murciano-Granadina goats

Morphological traits are of great importance to dairy goat production given their effect on phenotypes of economic interest. However, their underlying genomic architecture has not yet been extensively characterized. Herein, we aimed to identify genomic regions associated with body, udder, and leg conformation traits recorded in 825 Murciano-Granadina goats. We genotyped this resource population using the GoatSNP50 BeadChip (Illumina Inc., San Diego, CA) and performed genome-wide association analyses using the GEMMA software. We found 2 genome-wide significant associations between markers rs268273468 [Capra hircus (CHI) 16:69617700] and rs268249346 (CHI 28:18321523) and medial suspensory ligament. In contrast, we did not detect any genome-wide significant associations for body and leg traits. Moreover, we found 12, 19, and 7 chromosome-wide significant associations for udder, body, and leg traits, respectively. Comparison of our data with previous studies revealed a low level of positional concordance between regions associated with morphological traits. In addition to technical factors, this lack of concordance could be due to a substantial level of genetic heterogeneity among breeds or to the strong polygenic background of morphological traits, which makes it difficult to detect genetic factors that have small phenotypic effects.

A Genome-wide Association Study for Concussion Risk.

This study aimed to screen the entire genome for genetic markers associated with risk for concussion. A genome-wide association analyses was performed using data from the Kaiser Permanente Research Bank and the UK Biobank. Concussion cases were identified based on electronic health records from the Kaiser Permanente Research Bank and the UK Biobank from individuals of European ancestry. Genome-wide association analyses from both cohorts were tested for concussion using a logistic regression model adjusting for sex, height, weight, and race/ethnicity using allele counts for single nucleotide polymorphisms. Previously identified genes within the literature were also tested for association with concussion. There were a total of 4064 cases of concussion and 291,472 controls within the databases, with two single nucleotide polymorphisms demonstrating a genome-wide significant association with concussion. The first polymorphism, rs144663795 (P = 9.7 × 10-11; OR = 2.91 per allele copy), is located within the intron of SPATA5. Strong, deleterious mutations in SPATA5 cause intellectual disability, hearing loss, and vision loss. The second polymorphism, rs117985931 (P = 3.97 × 10-9; OR = 3.59 per allele copy), is located within PLXNA4. PLXNA4 plays a key role is axon outgrowth during neural development, and DNA variants in PLXNA4 are associated with risk for Alzheimer's disease. Previous investigations have identified five candidate genes that may be associated with concussion, but none showed a significant association in the current model (P < 0.05). Two genetic markers were identified as potential risk factors for concussion and deserve further validation and investigation of molecular mechanisms.