Genome-wide Significance Level Research Articles

Genome-Wide Association Study and Polygenic Risk Scores of Serum DHEAS Levels in a Chilean Children Cohort.

Adrenarche reflects the developmental growth of the adrenal zona reticularis, which produces increasing adrenal androgen secretion (eg, dehydroepiandrosterone [DHEA]/dehydroepiandrosterone sulfate [DHEAS]) from approximately age 5 to 15 years. We hypothesized that the study of the genetic determinants associated with variations in serum DHEAS during adrenarche might detect genetic variants influencing the rate or timing of this process. Genome-wide genotyping was performed in participants of the Chilean pediatric Growth and Obesity Chilean Cohort Study (GOCS) cohort (n = 788). We evaluated the genetic determinants of DHEAS levels at the genome-wide level and in targeted genes associated with steroidogenesis. To corroborate our findings, we evaluated a polygenic risk score (PRS) for age at pubarche, based on the discovered variants, in children from the same cohort. We identified one significant variant at the genome-wide level in the full cohort, close to the GALR1 gene (P = 3.81 × 10-8). In addition, variants suggestive of association (P < 1 × 10-5) were observed in PRLR, PITX1, PTPRD, NR1H4, and BCL11B. Stratifying by sex, we found variants suggestive of association in SERBP1 and CAMTA1/VAMP3 for boys and near ZNF98, TRPC6, and SULT2A1 for girls. We also found significant reductions in age at pubarche in those children with higher PRS for greater DHEAS based on these newly identified variants. Our results disclose one variant associated with DHEAS concentrations at the level of genome-wide association study significance, and several variants with a suggestive association that may be involved in the genetic regulation of adrenarche.

Pleiotropic predisposition to Alzheimer's disease and educational attainment: insights from the summary statistics analysis.

Epidemiological studies report beneficial associations of higher educational attainment (EDU) with Alzheimer’s disease (AD). Prior genome-wide association studies (GWAS) also reported variants associated with AD and EDU separately. The analysis of pleiotropic associations with these phenotypes may shed light on EDU-related protection against AD. We performed pleiotropic meta-analyses using Fisher’s method and omnibus test applied to summary statistics for single nucleotide polymorphisms (SNPs) associated with AD and EDU in large-scale univariate GWAS at suggestive-effect (5 × 10−8 < p < 0.1) and genome-wide (p ≤ 5 × 10−8) significance levels. We report 53 SNPs that attained p ≤ 5 × 10−8 at least in one of the pleiotropic meta-analyses and were reported in the univariate GWAS at 5 × 10−8 < p < 0.1. Of them, there were 46 pleiotropic SNPs according to Fisher’s method. Additionally, Fisher’s method identified 25 of 206 SNPs with pleiotropic effects, which attained p ≤ 5 × 10−8 in the univariate GWAS. We showed that a large fraction of the pleiotropic associations was affected by a counterintuitive phenomenon of antagonistic genetic heterogeneity, which explains the increase, rather than decrease, of the significance of the pleiotropic associations in the omnibus test. Functional enrichment analysis showed that apart from cancers, gene set harboring the non-pleiotropic SNPs was characterized by late-onset AD and neurodevelopmental disorders. The pleiotropic gene set was characterized by a broad spectrum of progressive neurological and neuromuscular diseases and immune-mediated conditions, including progressive motor neuropathy, multiple sclerosis, Parkinson’s disease, and severe AD. Our results suggest that disentangling genes harboring variants with and without pleiotropic associations with AD and EDU is promising for dissecting heterogeneity in biological mechanisms of AD.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11357-021-00484-1.

ERAP1, ERAP2, and Two Copies of HLA-Aw19 Alleles Increase the Risk for Birdshot Chorioretinopathy in HLA-A29 Carriers.

PurposeBirdshot chorioretinopathy (BSCR) is strongly associated with HLA-A29. This study was designed to elucidate the genetic modifiers of BSCR in HLA-A29 carriers.MethodsWe sequenced the largest BSCR cohort to date, including 286 cases and 108 HLA-A29–positive controls to determine genome-wide common and rare variant associations. We further typed the HLA alleles of cases and 45,386 HLA-A29 controls of European ancestry to identify HLA alleles that associate with BSCR risk.ResultsCarrying a second allele that belongs to the HLA-Aw19 broad antigen family (including HLA-A29, -A30, -A31, and -A33) increases the risk for BSCR (odds ratio [OR] = 4.44; P = 2.2e-03). This result was validated by comparing allele frequencies to large HLA-A29-controlled cohorts (n = 45,386; OR > 2.5; P < 1.3e-06). We also confirm that ERAP1 and ERAP2 haplotypes modulate disease risk. A meta-analysis with an independent dataset confirmed that ERAP1 and ERAP2 haplotypes modulate the risk for disease at a genome-wide significant level: ERAP1-rs27432 (OR = 2.46; 95% confidence interval [CI], 1.85–3.26; P = 4.07e-10), an expression quantitative trait locus (eQTL) decreasing ERAP1 expression; and ERAP2-rs10044354 (OR = 1.95; 95% CI, 1.55–2.44; P = 6.2e-09), an eQTL increasing ERAP2 expression. Furthermore, ERAP2-rs2248374 that disrupts ERAP2 expression is protective (OR = 0.56; 95% CI, 0.45–0.70; P = 2.39e-07). BSCR risk is additively increased when combining ERAP1/ERAP2 risk genotypes with two copies of HLA-Aw19 alleles (OR = 13.53; 95% CI, 3.79–54.77; P = 1.17e-05).ConclusionsThe genetic factors increasing BSCR risk demonstrate a pattern of increased processing, as well as increased presentation of ERAP2-specific peptides. This suggests a mechanism in which exceeding a peptide presentation threshold activates the immune response in choroids of A29 carriers.

Coffee and Caffeine Consumption and Risk of Kidney Stones: A Mendelian Randomization Study

Coffee and caffeine consumption have been associated with a lower risk of kidney stones in observational studies. We conducted a Mendelian randomization study to assess the causal nature of these associations. Mendelian randomization analysis. Independent genetic variants associated with coffee and caffeine consumption at the genome-wide significance level were selected from previously published meta-analyses as instrumental variables. Summary-level data for kidney stones were obtained from the UK Biobank study (6,536 cases and 388,508 noncases) and the FinnGen consortium (3,856 cases and 172,757 noncases). Genetically predicted coffee and caffeine consumption. Clinically diagnosed kidney stones. Mendelian randomization methods were used to calculate causal estimates. Estimates from the 2 sources were combined using the fixed-effects meta-analysis methods. Genetically predicted coffee and caffeine consumption was associated with a lower risk of kidney stones in the UK Biobank study, and the associations were directionally similar in the FinnGen consortium. The combined odds ratio of kidney stones was 0.60 (95% CI, 0.46-0.79; P< 0.001) per a genetically predicted 50% increase in coffee consumption and 0.81 (95% CI, 0.69-0.94; P= 0.005) per a genetically predicted 80-mg increase in caffeine consumption. Genetic influence on kidney stone risk via pathways not involving coffee or caffeine. Using genetic data, this study provides evidence that higher coffee and caffeine consumption may cause a reduction in kidney stones.

Genome-Wide Meta-analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas.

OBJECTIVESulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However, there exists significant variability in glycemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA1c reduction.RESEARCH DESIGN AND METHODSAs an initiative of the Metformin Genetics Plus Consortium (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortium, 5,485 White Europeans with type 2 diabetes treated with sulfonylureas were recruited from six referral centers in Europe and North America. We first estimated heritability using the generalized restricted maximum likelihood approach and then undertook genome-wide association studies of glycemic response to sulfonylureas measured as HbA1c reduction after 12 months of therapy followed by meta-analysis. These results were supported by acute glipizide challenge in humans who were naïve to type 2 diabetes medications, cis expression quantitative trait loci (eQTL), and functional validation in cellular models. Finally, we examined for possible drug-drug-gene interactions.RESULTSAfter establishing that sulfonylurea response is heritable (mean ± SEM 37 ± 11%), we identified two independent loci near the GXYLT1 and SLCO1B1 genes associated with HbA1c reduction at a genome-wide scale (P < 5 × 10−8). The C allele at rs1234032, near GXYLT1, was associated with 0.14% (1.5 mmol/mol), P = 2.39 × 10−8), lower reduction in HbA1c. Similarly, the C allele was associated with higher glucose trough levels (β = 1.61, P = 0.005) in healthy volunteers in the SUGAR-MGH given glipizide (N = 857). In 3,029 human whole blood samples, the C allele is a cis eQTL for increased expression of GXYLT1 (β = 0.21, P = 2.04 × 10−58). The C allele of rs10770791, in an intronic region of SLCO1B1, was associated with 0.11% (1.2 mmol/mol) greater reduction in HbA1c (P = 4.80 × 10−8). In 1,183 human liver samples, the C allele at rs10770791 is a cis eQTL for reduced SLCO1B1 expression (P = 1.61 × 10−7), which, together with functional studies in cells expressing SLCO1B1, supports a key role for hepatic SLCO1B1 (encoding OATP1B1) in regulation of sulfonylurea transport. Further, a significant interaction between statin use and SLCO1B1 genotype was observed (P = 0.001). In statin nonusers, C allele homozygotes at rs10770791 had a large absolute reduction in HbA1c (0.48 ± 0.12% [5.2 ± 1.26 mmol/mol]), equivalent to that associated with initiation of a dipeptidyl peptidase 4 inhibitor.CONCLUSIONSWe have identified clinically important genetic effects at genome-wide levels of significance, and important drug-drug-gene interactions, which include commonly prescribed statins. With increasing availability of genetic data embedded in clinical records these findings will be important in prescribing glucose-lowering drugs.

Translation From Genes to Mechanism in Schizophrenia: Are Immune–Synaptic Interactions the Missing Link?

Schizophrenia is associated with a striking range of biological alterations across multiple systems, suggesting that it could be considered a multisystem disorder (1). This is seen at the genetic level, where more than 200 loci implicating disparate genes implicating multiple molecular pathways have been associated with an increased risk of schizophrenia at a genome-wide significance level. It is also seen in the immune system, where a large and growing body of evidence demonstrates significant alterations in immune measures in schizophrenia (1).

Sleep-disordered breathing-related symptoms and risk of stroke: cohort study and Mendelian randomization analysis

BackgroundSleep-disordered breathing (SDB) may contribute to development of stroke. However, findings are inconclusive. We investigated whether SDB-related symptoms are associated with incidence of stroke and its types in a general community sample of adult men and women as well as to perform Mendelian randomization (MR) analysis.MethodsWe used data from a cohort of 41,742 Swedish adults (56–94 years of age) who completed questionnaires regarding snoring, cessation of breathing, lifestyle and health characteristics. Participants were followed up for incident stroke and death over 8 years through linkage to the Swedish Registers. Hazard ratios, adjusted for potential confounders, were estimated by Cox proportional hazards regression. MR analyses were performed using single-nucleotide polymorphisms associated with sleep apnea at the genome-wide significance level and summary-level data for stroke and its subtypes from consortia and a meta-analysis of Genome-Wide Association Studies.ResultsIn the cohort study, symptoms of disturbing snoring and/or cessation of breathing were associated with increased risk of total stroke (hazard ratio 1.12, 95% confidence interval 1.02–1.24) and intracerebral hemorrhage (hazard ratio 1.59, 95% confidence interval 1.23–2.05) but not with ischemic stroke or subarachnoid hemorrhage. MR analyses showed no association of genetic liability to sleep apnea with the risk of overall stroke or any specific types of stroke or ischemic stroke subtypes.ConclusionsSDB-related symptoms were associated with increased risk of total stroke, specifically intracerebral hemorrhage, in the observational analyses but not in the MR analyses. There was limited evidence of an association of SDB with ischemic stroke and subarachnoid hemorrhage.

Heritability and genome-wide association study of blood pressure in Chinese adult twins.

BackgroundBlood pressure (BP) is an independent and important factor for chronic diseases such as cardiovascular diseases and diabetes.MethodsWe firstly conducted twin modeling analyses to explore the heritability of BP, including systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP) and mean arterial pressure (MAP), and then performed genome‐wide association studies to explore the associated genomic loci, genes, and pathways.ResultsA total of 380 Chinese twin pairs were included. The AE model containing additive genetic parameter (A) and unique/non‐shared environmental parameter (E) was the best fit model, with A accounting for 53.7%, 50.1%, 48.1%, and 53.3% for SBP, DBP, PP and MAP, respectively. No SNP was found to reach the genome‐wide significance level (p < 5 × 10−8), however, three, four, 14 and nine SNPs were found to exceed suggestive significance level (p < 1 × 10−5) for SBP, DBP, PP, and MAP, respectively. And after imputation, 46, 37, 91 and 61 SNPs were found to exceed the suggestive significance level for SBP, DBP, PP, and MAP, respectively. In gene‐based analysis, 53 common genes were found among SBP, DBP, PP, and MAP. In pathway enrichment analysis, 672, 706, 701, and 596 biological pathways were associated with SBP, DBP, PP, and MAP, respectively (p < 0.05).ConclusionOur study suggests that BP is moderately heritable in the Chinese population and could be mediated by a series of genomic loci, genes, and pathways. Future larger‐scale studies are needed to confirm our findings.

Whole-milk consumption decreases the risk of inflammatory bowel disease: a two-sample Mendelian randomization analysis

Objective: The impact of dairy fat on inflammatory bowel disease remained inconclusive. We aimed to compare the effects of whole-milk and skimmed-milk consumption on the risk of inflammatory bowel disease using a Mendelian randomization analysis. Methods: We conducted a genome-wide association study of the preference for whole versus skimmed milk using data for 20,200 whole-milk consumers and 67,847 skimmed-milk consumers from the UK Biobank. The lead single nucleotide polymorphisms in the associated loci were identified at the genome-wide significance level, and were further employed as instrumental variables for whole-milk preference. We conducted a two-sample Mendelian randomization analysis with whole-milk preference as the exposure and inflammatory bowel disease as the outcome. The pleiotropic effects and heterogeneity of the instrumental variables were estimated using Mendelian randomization-Egger regression and Cochran Q test, respectively. This study was conducted using the UKB resources under the application "53536" . The UK Biobank was approved by the North West Multi-center Research Ethics Committee, the National Information Governance Board for Health and Social Care in England and Wales, and the Community Health Index Advisory Group in Scotland. Results: The genome-wide association study identified five lead nucleotide polymorphisms associated with whole-milk preference. Mendelian randomization indicated that whole-milk preference significantly decreased the risk of inflammatory bowel disease ( β =-1.735, P =0.048). Of the two subtypes, whole-milk preference was associated with a lower risk of Crohn disease ( β =-2.549, P =0.032), but had no significant effect on the risk of ulcerative colitis ( β =-1.002, P =0.44). Conclusion: Consumption of whole-milk fat may protect against Crohn disease, compared with skimmed milk. This conclusion was based on causal inference in a cohort study, and further validation in randomized controlled trials is warranted.

Genome-wide association study reveals a quantitative trait locus and two candidate genes on Sus scrofa chromosome 5 affecting intramuscular fat content in Suhuai pigs

Intramuscular fat content (IFC) is an essential quantitative trait of meat, affecting multiple meat quality indicators. A certain amount of IFC could not only improve the sensory score of pork but also increase the flavour, tenderness, juiciness and shelf-life. To dissect the genetic determinants of IFC, two methods, including genome-wide efficient mixed-model analysis (GEMMA) and linkage disequilibrium adjusted kinships (LDAKs), were used to carry out genome-wide association studies for IFC in Suhuai pig population. A total of 14 and 18 significant single nucleotide polymorphisms (SNPs) were identified by GEMMA and LDAK, respectively. The results of these two methods were highly consistent and all 14 significant SNPs in GEMMA were detected by LDAK. Seven of the 18 SNPs reached the genome-wide significance level (P < 9.85E−07) while 11 cases reached the suggestive significance level (P < 1.77E−05). These significant SNPs were mainly distributed on Sus scrofa chromosome (SSC) 5, 3, and 7. Moreover, one locus resides in a 2.27 Mb (71.37–73.64 Mb) region on SSC5 harbouring 13 significant SNPs associated with IFC, and the lead SNP (rs81302978) also locates in this region. Linkage disequilibrium (LD) analysis showed that there were four pairs of complete LD (r2 = 1) among these 13 SNPs, and the remaining 9 SNPs with incomplete LD (r2 ≠ 1) were selected for subsequent analyses of IFC. Association analyses showed that 7 out of 9 SNPs were significantly associated with IFC (P < 0.05) in 330 Suhuai pigs, and the other 2 SNPs tended to reach a significant association level with IFC (P < 0.1). The phenotypic variance explained (PVE) range of these 9 SNPs was 0.92–3.55%. Meanwhile, the lead SNP was also significantly associated (rs81302978) with IFC (P < 0.05) in 378 commercial hybrid pigs (Pietrain × Duroc) × (Landrace × Yorkshire) (PDLY), and the PVE was 1.38%. Besides, two lipid metabolism-relevant candidate genes, the leucine rich repeat kinase 2 (LRRK2) and PDZ domain containing ring finger 4 (PDZRN4) were identified in the 2.27 Mb region on SSC5. In conclusion, our results may provide a set of markers useful for genetic improvement of IFC in pigs and will advance the genome selection process of IFC on pig breeding programmes.

Genome-wide Association Study of Lipid Traits in Youth With Type 2 Diabetes.

ContextDyslipidemia is highly prevalent in youth with type 2 diabetes (T2D), yet the pathogenic components of dyslipidemia in youth with T2D are poorly understood.ObjectiveTo evaluate the genetic determinants of lipid traits in youth with T2D through a genome-wide association study.Design, Participants, and Main Outcome MeasuresWe genotyped 206 928 variants and imputed 17 642 824 variants in 1076 youth (mean age 15.0 ± 2.48 years) with T2D from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) and SEARCH for Diabetes in Youth (SEARCH) studies as part of the Progress in Diabetes Genetics in Youth (ProDiGY) consortium. We performed association testing for triglyceride and low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (HDL-c) concentrations adjusted for the genetic relationship matrix within each substudy followed by meta-analyses for each trait.ResultsWe identified a novel association between a deletion on chromosome 3 (3:67817380_AT/A_Deletion:RP11-81N13.1) and triglyceride levels at genome-wide level of significance (P = 2.3 × 10−8) with each risk allele increasing triglycerides by 20%. We also identified a genome-wide significant signal at rs247617 (P = 5.1 × 10−9) between HERFUD1 and CETP associated with HDL-c, with carriers of 1 copy of the risk allele having twice higher HDL-c.ConclusionsOur genetic analyses of lipid traits in youth with T2D have identified 1 novel and 1 previously known locus. Additional studies are needed to further characterize the genetic architecture of dyslipidemia in youth with T2D.

Maternal selenium levels and whole genome screen in recurrent spontaneous preterm birth population: A nested case control study

ObjectiveTo establish if low maternal selenium (Se) was associated with sPTB in women with recurrent sPTB and identify genetic link with maternal Se levels. DesignNested case-control study. SettingTertiary Maternity Hospital. PopulationPlasma and whole blood from pregnant women with history of early sPTB/PPROM < 34+0 and European ancestry were obtained at 20 weeks (range 15–24 weeks). ‘Cases’ were recurrent PTB/PPROM < 34+0 weeks and term (≥37+0) deliveries were classified as ‘high-risk controls.’ Women with previous term births and index birth ≥ 39 weeks were ‘low-risk controls’. MethodsMaternal plasma Se measured by ICP-MS was used as a continuous phenotype in a GWAS analysis. Se was added to a logistic regression model using PTB predictor variables. Main outcome measuresMaternal Se concentration, recurrent early sPTB/PPROM. Results53/177 high-risk women had a recurrent sPTB/PPROM < 34+0weeks and were 2.7 times more likely to have a Se level < 83.3 ppm at 20weeks of pregnancy compared with low-risk term controls (n = 179), (RR 2.7, 95%CI 1.5–4.8; p = .001). One SNP from a non-coding region (FOXN3 intron variant, rs55793422) reached genome-wide significance level (p = 3.73E−08). Targeted analysis of Se gene variant did not show difference between preterm and term births. (χ2 test, OR = 0.95; 95%CI = 0.59–1.56; p = 0.82). When Se levels were added to a clinical prediction model, only an additional 5% of cases (n = 3) and 0.6% (n = 1) of controls were correctly identified. ConclusionsLow plasma Se is associated with sPTB risk but is not sufficiently predictive at individual patient level. We did not find a genetic association between maternal Se levels and Se-related genes.

Graves' Disease and Rheumatoid Arthritis: A Bidirectional Mendelian Randomization Study.

BackgroundThe frequent coexistence of Graves’ disease (GD) and rheumatoid arthritis (RA) has been cited and discussed in observational studies, but it remains a question as to whether there is a causal effect between the two diseases.MethodsWe retrieved genome-wide association study (GWAS) summary data of GD and RA from BioBank Japan (BBJ). Single nucleotide polymorphisms (SNPs) associated with diseases of interest were selected as instrumental variables (IVs) at a genome-wide significance level (P < 5.0 × 10−8). The random-effects inverse variance weighted method (IVW) was used to combine the causal effect of IVs. The horizontal pleiotropy effect was analyzed by MR-Egger and weighted median method sensitivity test. A leave-one-out analysis was conducted to avoid bias caused by a single SNP. The statistical power of our MR result was calculated according to Brion’s method.ResultsOur study discovered a bidirectional causal effect between GD and RA. The presence of RA may increase the risk of GD by 39% (OR 1.39, 95% CI 1.10–1.75, P = 0.007). Similarly, the existence of GD may increase the risk of RA by 30% (OR 1.30, 95% CI 0.94–1.80, P = 0.112). Our study provides 100% power to detect the causal effect of RA on GD risk, and vice versa.ConclusionsWe found a bidirectional causal effect between GD and RA in an Asian population. Our study supported the clinical need for screening GD in RA patients, and vice versa. The potential benefit of sound management of RA in GD patients (or GD in RA patients) merits excellent attention. Moreover, novel satisfactory medicine for RA may be applicable to GD and such potential is worthy of further investigation.

Effect of Metabolite Levels on Type 2 Diabetes Mellitus and Glycemic Traits: A Mendelian Randomization Study.

To assess the causal associations of plasma levels of metabolites with type 2 diabetes mellitus (T2DM) and glycemic traits. Two-sample mendelian randomization (MR) was conducted to assess the causal associations. Genetic variants strongly associated with metabolites at genome-wide significance level (P < 5 × 10-8) were selected from public genome-wide association studies, and single-nucleotide polymorphisms of outcomes were obtained from the Diabetes Genetics Replication and Meta-analysis consortium for T2DM and from the Meta-Analyses of Glucose and Insulin-related Traits Consortium for fasting glucose, insulin, and glycated hemoglobin (HbA1c). The Wald ratio and inverse-variance weighted methods were used for analyses, and MR-Egger was used for sensitivity analysis. The β estimates per 1-SD increase of arachidonic acid (AA) level was 0.16 (95% CI, 0.078-0.242; P < 0.001). Genetic predisposition to higher plasma AA levels were associated with higher fasting glucose levels (β 0.10 [95% CI, 0.064-0.134], P < 0.001), higher HbA1c levels (β 0.04 [95% CI, 0.027-0.061]), and lower fasting insulin levels (β -0.025 [95% CI, -0.047 to -0.002], P = 0.033). Besides, 2-hydroxybutyric acid (2-HBA) might have a positive causal effect on glycemic traits. Our findings suggest that AA and 2-HBA may have causal associations on T2DM and glycemic traits. This is beneficial for clarifying the pathogenesis of T2DM, which would be valuable for early identification and prevention for T2DM.

Genetic Determinants of Increased Body Mass Index Partially Mediate the Effect of Elevated Birth Weight on the Increased Risk of Atrial Fibrillation.

Background: Although several observational studies have shown an association between birth weight (BW) and atrial fibrillation (AF), controversy remains. In this study, we aimed to explore the role of elevated BW on the etiology of AF.Methods: A two-sample Mendelian randomization (MR) study was designed to infer the causality. The genetic data on the associations of single-nucleotide polymorphisms (SNPs) with BW and AF were separately obtained from two large-scale genome-wide association studies with up to 321,223 and 1,030,836 individuals, respectively. SNPs were identified at a genome-wide significant level (p <5 × 10−8). The inverse variance-weighted (IVW) method was employed to obtain causal estimates as our primary analysis. Sensitivity analyses with various statistical methods were applied to evaluate the robustness of the results, and multivariable MR analysis was conducted to determine whether this association was mediated by the body mass index (BMI).Results: In total, 144 SNPs were identified as the genetic instrumental variables. MR analysis revealed a causal effect of elevated BW on AF (OR = 1.27, 95% CI = 1.14–1.40, p = 5.70 × 10−6). All the results in sensitivity analyses were consistent with the primary result. The effect of BW on AF was attenuated when adjusted for BMI (OR = 1.16, 95% CI = 1.01–1.33, p = 0.04).Conclusions: This study indicated that elevated BW was significantly associated with increased lifelong risk of AF, which may be partially mediated by BMI.

QTL mapping in outbred tetraploid (and diploid) diallel populations.

Over the last decade, multiparental populations have become a mainstay of genetics research in diploid species. Our goal was to extend this paradigm to autotetraploids by developing software for quantitative trait locus (QTL) mapping in connected F1 populations derived from a set of shared parents. For QTL discovery, phenotypes are regressed on the dosage of parental haplotypes to estimate additive effects. Statistical properties of the model were explored by simulating half-diallel diploid and tetraploid populations with different population sizes and numbers of parents. Across scenarios, the number of progeny per parental haplotype (pph) largely determined the statistical power for QTL detection and accuracy of the estimated haplotype effects. Multiallelic QTL with heritability 0.2 were detected with 90% probability at 25 pph and genome-wide significance level 0.05, and the additive haplotype effects were estimated with over 90% accuracy. Following QTL discovery, the software enables a comparison of models with multiple QTL and nonadditive effects. To illustrate, we analyzed potato tuber shape in a half-diallel population with three tetraploid parents. A well-known QTL on chromosome 10 was detected, for which the inclusion of digenic dominance lowered the Deviance Information Criterion (DIC) by 17 points compared to the additive model. The final model also contained a minor QTL on chromosome 1, but higher-order dominance and epistatic effects were excluded based on the DIC. In terms of practical impacts, the software is already being used to select offspring based on the effect and dosage of particular haplotypes in breeding programs.

Association of Variants Near the Bradykinin Receptor B2 Gene With Angioedema in Patients Taking ACE Inhibitors

BackgroundAngioedema is a rare but potentially life-threatening adverse reaction associated with angiotensin-converting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients. ObjectivesThe aim of this study was to identify genetic factors associated with ACE inhibitor–associated angioedema. MethodsA genomewide association study involving patients of European descent, all taking ACE inhibitors, was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as subjects with angioedema events and filled prescriptions for ACE inhibitors ≤180 days before the events. Control subjects were defined as those with continuous treatment with ACE inhibitors without any history of angioedema. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for angioedema risk using logistic mixed model regression analysis. Summary statistics from the discovery and replication cohorts were analyzed using a fixed-effects meta-analysis model. ResultsThe discovery cohort consisted of 462 cases and 53,391 ACE inhibitor–treated control subjects. The replication cohort consisted of 142 cases and 1,345 ACE inhibitor–treated control subjects. In the discovery cohort, 1 locus, residing at chromosome 14q32.2, was identified that associated with angioedema at the genomewide significance level of P <5 × 10–8. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR: 1.62; 95% CI: 1.38 to 1.90; P = 4.3 × 10−9). This variant was validated in our replication cohort with a similar direction and effect size (OR: 1.60; 95% CI: 1.13 to 2.25; P = 7.2 × 10−3). We found that carriers of the risk allele had significantly lower systolic (−0.46 mm Hg per T allele; 95% CI: −0.83 to −0.10; P = 0.013) and diastolic (−0.26 mm Hg per T allele; 95% CI: −0.46 to −0.05; P = 0.013) blood pressure. ConclusionsIn this genomewide association study involving individuals treated with ACE inhibitors, we found that common variants located in close proximity to the bradykinin receptor B2 gene were associated with increased risk for ACE inhibitor–related angioedema.

Assessing the role of cortisol in cancer: a wide-ranged Mendelian randomisation study.

Cortisol's immunosuppressive, obesogenic, and hyperglycaemic effects suggest that it may play a role in cancer development. However, whether cortisol increases cancer risk is not known. We investigated the potential causal association between plasma cortisol and risk of overall and common site-specific cancers using Mendelian randomisation. Three genetic variants associated with morning plasma cortisol levels at the genome-wide significance level (P < 5 × 10-8) in the Cortisol Network consortium were used as genetic instruments. Summary-level genome-wide association study data for the cancer outcomes were obtained from large-scale cancer consortia, the UK Biobank, and the FinnGen consortium. Two-sample Mendelian randomisation analyses were performed using the fixed-effects inverse-variance weighted method. Estimates across data sources were combined using meta-analysis. A standard deviation increase in genetically predicted plasma cortisol was associated with increased risk of endometrial cancer (odds ratio 1.50, 95% confidence interval 1.13-1.99; P = 0.005). There was no significant association between genetically predicted plasma cortisol and risk of other common site-specific cancers, including breast, ovarian, prostate, colorectal, lung, or malignant skin cancer, or overall cancer. These results indicate that elevated plasma cortisol levels may increase the risk of endometrial cancer but not other cancers. The mechanism by which this occurs remains to be investigated.

A Genome-Wide Association Study of Age-Related Hearing Impairment in Middle- and Old-Aged Chinese Twins.

Background Age-related hearing impairment (ARHI) is considered an unpreventable disorder. We aimed to detect specific genetic variants that are potentially related to ARHI via genome-wide association study (GWAS). Methods A sample of 131 dizygotic twins was genotyped for single-nucleotide polymorphism- (SNP-) based GWAS. Gene-based test was performed using VEGAS2. Pathway enrichment analysis was conducted by PASCAL. Results The twins are with a median age of 49 years, of which 128 were females and 134 were males. rs6633657 was the only SNP that reached the genome-wide significance level for better ear hearing level (BEHL) at 2.0 kHz (P = 1.19 × 10−8). Totally, 9, 10, 42, 7, 17, and 5 SNPs were suggestive evidence level for (P < 1 × 10−5) BEHLs at 0.5, 1.0, 2.0, 4.0, and 8.0 kHz and pure tone average (PTA), respectively. Several promising genetic regions in chromosomes (near the C20orf196, AQPEP, UBQLN3, OR51B5, OR51I2, OR52D1, GLTP, GIT2, and PARK2) nominally associated with ARHI were identified. Gene-based analysis revealed 165, 173, 77, 178, 170, and 145 genes nominally associated with BEHLs at 0.5, 1.0, 2.0, 4.0, and 8.0 kHz and PTA, respectively (P < 0.05). For BEHLs at 0.5, 1.0, and 2.0 kHz, the main enriched pathways were phosphatidylinositol signaling system, regulation of ornithine decarboxylase, eukaryotic translation initiation factor (EIF) pathway, amine compound solute carrier (SLC) transporters, synthesis of phosphoinositides (PIPS) at the plasma membrane, and phosphatidylinositols (PI) metabolism. Conclusions The genetic variations reported herein are significantly involved in functional genes and regulatory domains that mediate ARHI pathogenesis. These findings provide clues for the further unraveling of the molecular physiology of hearing functions and identifying novel diagnostic biomarkers and therapeutic targets of ARHI.

Genome-wide association study in the Taiwan Biobank identifies four novel genes for human height: NABP2, RASA2, RNF41 and SLC39A5.

Numerous genome-wide association studies (GWASs) have been conducted for the identification of genetic variants involved with human height. The vast majority of these studies, however, have been conducted in populations of European ancestry. Here, we report the first GWAS of adult height in the Taiwan Biobank using a discovery sample of 14 571 individuals and an independent replication sample of 20 506 individuals. From our analysis, we generalize to the Taiwanese population genome-wide significant associations with height and 18 previously identified genes in European and non-Taiwanese East Asian populations. We also identify and replicate, at the genome-wide significance level, associated variants for height in four novel genes at two loci that have not previously been reported: RASA2 on chromosome 3 and NABP2, RNF41 and SLC39A5 at 12q13.3 on chromosome 12. RASA2 and RNF41 are strong candidates for having a role in height with copy number and loss of function variants in RASA2 previously found to be associated with short stature disorders, and decreased expression of the RNF41 gene resulting in insulin resistance in skeletal muscle. The results from our analysis of the Taiwan Biobank underscore the potential for the identification of novel genetic discoveries in underrepresented worldwide populations, even for traits, such as height, that have been extensively investigated in large-scale studies of European ancestry populations.