European-ancestry Genome-wide Association Studies Research Articles

Type 2 diabetes mellitus and cardiovascular health: Evidence of causal relationships in a European ancestry population.

Type 2 diabetes mellitus (T2DM) is associated with increased cardiovascular disease (CVD) risk, but whether T2DM directly causes adverse cardiac remodelling is uncertain. We performed a comprehensive Mendelian randomization (MR) analysis to investigate the causal relevance of T2DM to CVD outcomes and cardiac structure/function. Bidirectional two-sample MR was conducted using summary-level data from European-ancestry genome-wide association studies. The T2DM GWAS data included 80154 cases and 853816 controls from the DIAGRAM consortium. Outcomes included coronary artery disease (CAD), myocardial infarction (MI), stroke, heart failure, atrial fibrillation, and various quantitative cardiac imaging traits assessed by magnetic resonance imaging. MR analysis revealed causal associations between genetic predisposition to T2DM and increased risk of CAD (odds ratio [OR] 1.104, 95% confidence interval [CI] 1.078-1.130, P=2.59e-16), MI (OR 1.129, 95% CI 1.094-1.166, P=6.02e-14) and stroke (OR 1.086, 95% CI 1.064-1.109, P=1.02e-14). These associations were validated in the FinnGen cohort (CAD: OR 1.117, 95% CI 1.075-1.158, P=1.56e-9; MI: OR 1.132, 95% CI 1.083-1.184, P=4.27e-8; stroke: OR 1.138, 95% CI 1.107-1.170, P=3.52e-20). Multivariable MR show consistent findings (CAD: OR 1.063, 95% CI 1.031-1.097, P=1.11e-4; MI: OR 1.088, 95% CI 1.042-1.135, P=1.12e-4; stroke: OR 1.066, 95% CI 1.032-1.101, P=1.18e-4) after adjusting for cardiometabolic traits. T2DM was causally associated with higher left ventricular mass index (β=0.473, 95% CI 0.193 to 0.752, P=0.001), lower indexed right atrial minimum (β=-0.048, 95% CI -0.073 to -0.022, P=2.1e-5), and maximum (β=-0.042, 95% CI -0.065 to -0.019, P=4.12e-5) areas. The effects on right atrial size remained significant after adjusting for risk factors (minimum area: β=-0.041, 95% CI -0.072 to -0.010, P=0.009; maximum area: β=-0.039, 95% CI -0.069 to -0.008, P=0.012). Both apolipoprotein A1 and SBP are important mediators in the causal relationship between T2DM and left ventricular mass index. No reverse causal associations were identified. Our MR study demonstrates that genetic liability to T2DM plays causal roles in CAD, MI, stroke, and cardiac structure changes including left ventricular hypertrophy and reduced right atrial dimensions. These findings provide genetic evidence supporting glycaemic control in T2DM to mitigate cardiovascular complications and adverse cardiac remodelling.

Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci.

Brugada syndrome (BrS) is an inherited arrhythmia with a higher disease prevalence and more lethal arrhythmic events in Asians than in Europeans. Genome-wide association studies (GWAS) have revealed its polygenic architecture mainly in European populations. The aim of this study was to identify novel BrS-associated loci and to compare allelic effects across ancestries. A GWAS was conducted in Japanese participants, involving 940 cases and 1634 controls, followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3760 cases and 11 635 controls). The novel loci were characterized by fine-mapping, gene expression, and splicing quantitative trait associations in the human heart. The Japanese-specific GWAS identified one novel locus near ZSCAN20 (P = 1.0 × 10-8), and the cross-ancestry meta-analysis identified 17 association signals, including six novel loci. The effect directions of the 17 lead variants were consistent (94.1%; P for sign test = 2.7 × 10-4), and their allelic effects were highly correlated across ancestries (Pearson's R = .91; P = 2.9 × 10-7). The genetic risk score derived from the BrS GWAS of European ancestry was significantly associated with the risk of BrS in the Japanese population [odds ratio 2.12 (95% confidence interval 1.94-2.31); P = 1.2 × 10-61], suggesting a shared genetic architecture across ancestries. Functional characterization revealed that a lead variant in CAMK2D promotes alternative splicing, resulting in an isoform switch of calmodulin kinase II-δ, favouring a pro-inflammatory/pro-death pathway. This study demonstrates novel susceptibility loci implicating potentially novel pathogenesis underlying BrS. Despite differences in clinical expressivity and epidemiology, the polygenic architecture of BrS was substantially shared across ancestries.

Genome‐wide Association Study Meta‐analysis of Neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration

AbstractBackgroundNeurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro‐axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels and its genetic correlation with neurological traits could therefore provide new insights into shared molecular mechanisms underlying neurodegenerative disorders.MethodTo identify the genetic variations underlying blood NfL levels, we conducted an ancestry‐specific meta‐analyses of genome‐wide association studies (GWAS) based on 18,532 participants from 11 cohorts of European and 1142 participants (3 cohorts) of African‐American ancestry. In the post‐GWAS analyses, we performed expression quantitative trait loci (eQTL) analysis, LD‐regression, and genetic risk score (GRS) association analysis with neurological traits.ResultIn the European ancestry GWAS meta‐analysis, we identified two genome‐wide significant (P< 5×10−8) loci at 16p12 (UMOD), and 17q24 (SLC39A11). In the African‐American ancestry GWAS meta‐analysis, we identified three novel loci at 1q43 (FMN2), 12q14, and 12q21. Genetic correlation based on the European ancestry meta‐analysis with neurological traits showed a strong genetic correlation of NfL with Alzheimer’s disease (AD) (rg = 0.32, P = 1.74×10−6), total‐tau (rg = 2.01, P = 1.03×10−6), amyloid‐beta (Aβ)‐40 (rg = 0.80, P = 6.92×10−6),and Aβ‐42 (rg = 1.03, P = 4.39×10−5). A higher genetic risk score based on NfL‐associated genetic variants was also related to increased plasma levels of total‐tau (P = 1.97×10−4), Aβ‐ 40 (P = 2.24×10−5), Aβ‐42 (P = 2.92×10−4) in the Rotterdam Study.ConclusionThis large‐scale GWAS meta‐analysis revealed multiple novel genetic loci of NfL levels in blood in participants from European and African‐American ancestry. Significant genetic correlation of genes underlying NfL with AD, Aβ‐42, and total‐tau may indicate a common underlying pathway of neurodegeneration.

Causal relationship between sleep traits and cognitive impairment: A Mendelian randomization study.

Observational studies had demonstrated a link between sleep disturbances and cognitive decline. Here, we aimed to investigate the causal association between genetically predicted sleep traits and cognitive impairment using Mendelian randomization (MR). Using strict criteria, we selected genetic variants from European ancestry Genome-wide association studies (GWAS) from the Sleep Disorders Knowledge Portal and UK Biobank as instrumental variables for several sleep traits, including insomnia, sleep duration, daytime sleepiness, daytime napping, and chronotype. Summary statistics related to cognitive impairment were derived from five different GWAS, including the Social Science Genetic Association Consortium. The role of self-reported sleep trait phenotypes in the etiology of cognitive impairment was explored using inverse-variance weighted (IVW) tests, MR-Egger tests, and weighted medians, and sensitivity analyses were conducted to ensure robustness. In the main IVW analysis, sleep duration (reaction time: β=-0.05, 95% CI -0.07 to -0.04, p=1.93×10-12 ), daytime sleepiness (average cortical thickness: β=-0.12, 95% CI -0.22 to -0.02, p=0.023), and daytime napping (fluid intelligence: β=-0.47, 95% CI -0.87 to -0.07, p=0.021; hippocampal volume in Alzheimer's disease: β=-0.99, 95% CI -1.64 to -0.35, p=0.002) were significantly negatively correlated with cognitive performance. However, any effects of insomnia and chronotype on cognitive impairment were not determined. Our findings highlighted that focusing on sleep behaviors or distinct sleep patterns-particularly sleep duration, daytime sleepiness, and daytime napping, was a promising approach for preventing cognitive impairment. This study also shed light on risk factors for and potential early markers of cognitive impairment risk factors.

Population-specific and cross-ancestry genome-wide association study identifies shared genetic architecture and 6 new risk loci including CAMK2D associated for Brugada syndrome

Abstract Introduction The Brugada syndrome (BrS) is an inherited arrhythmia characterized by coved-type ST-segment elevation in the right precordial leads and an increased risk for sudden cardiac death. Genome-wide association studies (GWAS) of BrS, mainly performed in European ancestry, have illustrated its complex genetic architecture as an polygenic disease besides a monogenic trait due to mutations in the major responsible cardiac sodium channel gene SCN5A. Clinical manifestations of BrS including the disease prevalence and the incidence of sudden death are known to be variable between Asian and European populations, however, its underlying mechanisms are largely unknown. Objectives We aimed to identify novel BrS-associated loci and to assess ancestry-dependent genetic heterogeneity that may underlie the variable clinical manifestations of BrS patients across different populations. Methods We performed a genome-wide meta-analysis of BrS in the Japanese ancestry (940 cases and 1,634 controls), followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3,760 cases and 11,635 controls) to identify novel risk loci and compared the allelic effects between two ancestries. We characterized the novel loci based on fine-mapping of potential causal variants, and expression and splicing quantitative trait associations using the Genotype-Tissue Expression (GTEx) database. Results The Japanese-specific genome-wide meta-analysis identified a novel association signal near the ZSCAN20 (lead variant, rs2336244; P=1.0E-08) besides previously reported 4 association signals at the SCN5A-SCN10A and HEY2 loci. Cross-ancestry genome-wide meta-analysis identified 17 association signals including 6 novel loci. The effect directions were consistent for 94.1% of the variants (16 of 17; P for sign test = 0.00027) and their allelic effects were highly correlated across ancestries (Pearson’s R=0.91 [P=2.9E-07]). The genetic risk score (GRS) derived from European-ancestry GWAS of BrS was significantly associated with the risk of BrS in the Japanese populations (odds ratio, 2.12 [95% confidence interval, 1.94–2.31]; P=1.2E-61), suggesting the shared genetic architecture across ancestries. The functional characterization of the 6 novel loci showed that one lead SNP on CAMK2D promotes an alternative splicing resulting in an isoform switch of calmodulin kinase II that favors up-regulation of the pro-inflammatory isoform δ9 and down-regulation of the pro-survival isoform δ3. Conclusions Our results identified 6 novel susceptible loci associated with BrS and revealed shared genetic architecture across ancestries.GWAS Manhattan plotShared genetic architecture

Founder population-specific weights yield improvements in performance of polygenic risk scores for Alzheimer disease in the Midwestern Amish

Alzheimer disease (AD) is the most common type of dementia and is estimated to affect 6 million Americans. Risk for AD is multifactorial, including both genetic and environmental risk factors. AD genomic research has generally focused on identification of risk variants. Using this information, polygenic risk scores (PRSs) can be calculated to quantify an individual's relative disease risk due to genetic factors. The Amish are a founder population descended from German and Swiss Anabaptist immigrants. They experienced a genetic bottleneck after arrival in the United States, making their genetic architecture different from the broader European ancestry population. Prior work has demonstrated the lack of transferability of PRSs across populations. Here, we compared the performance of PRSs derived from genome-wide association studies (GWASs) of Amish individuals to those derived from a large European ancestry GWAS. Participants were screened for cognitive impairment with further evaluation for AD. Genotype data were imputed after collection via Illumina genotyping arrays. The Amish individuals were split into two groups based on the primary site of recruitment. For each group, GWAS was conducted with account for relatedness and adjustment for covariates. PRSs were then calculated using weights from the other Amish group. PRS models were evaluated with and without covariates. The Amish-derived PRSs distinguished between dementia status better than the European-derived PRS in our Amish populations and demonstrated performance improvements despite a smaller training sample size. This work highlighted considerations for AD PRS usage in populations that cannot be adequately described by basic race/ethnicity or ancestry classifications.

Causal relationship between polycystic ovary syndrome and chronic kidney disease: A Mendelian randomization study.

Polycystic ovary syndrome is one of the most common endocrine disorders among women of childbearing age. The relationship between polycystic ovary syndrome and chronic kidney disease remains unclear and controversial. In this study, we investigated the causal role of polycystic ovary syndrome in the development of chronic kidney disease using the two-sample Mendelian randomization method. Public shared summary-level data was acquired from European-ancestry genome wide association studies. We finally obtained 12 single nucleotide polymorphisms as instrumental variables, which were associated with polycystic ovary syndrome in European at genome-wide significance (P < 5 × 10-8). Inverse-variance weighted method was employed in the Mendelian randomization analysis and multiple sensitivity analyses were implemented. Outcome data were obtained from the Open GWAS database. A positive causal association was observed between polycystic ovary syndrome and chronic kidney disease (odds ratio [OR]=1.180, 95% confidence interval [CI]: 1.038-1.342; P=0.010). Further analyses clarified that causal relationship exist between polycystic ovary syndrome and some serological indicators of chronic kidney disease (fibroblast growth factor 23: OR= 1.205, 95% CI: 1.031-1.409, P=0.019; creatinine: OR= 1.012, 95% CI: 1.001-1.023, P=0.035; cystatin C: OR= 1.024, 95% CI: 1.006-1.042, P=0.009). However, there was no causal association of polycystic ovary syndrome with other factors in the data sources we employed. Our results indicate an important role of polycystic ovary syndrome in the development of chronic kidney disease. This study suggests that regular follow-up of renal function in patients with polycystic ovary syndrome is necessary for the early treatment of chronic kidney disease.

Polygenic Risk Scores for Alzheimer's Disease and GeneralCognitive Function Are Associated With Measures of Cognition in Older South Asians.

Genome-wide association studies (GWAS) conducted in European ancestry (EA) have identified hundreds of single-nucleotide polymorphisms (SNPs) associated with general cognitive function and/or Alzheimer's disease (AD). The association between these SNPs and cognitive function has not been fully evaluated in populations with complex genetic substructure such as South Asians. This study investigated whether SNPs identified in EA GWAS, either individually or as polygenic risk scores (PRSs), were associated with general cognitive function and 5 broad cognitive domains in 932 South Asians from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD). We found that SNPs identified from AD GWAS were more strongly associated with cognitive function in LASI-DAD than those from a GWAS of general cognitive function. PRSs for general cognitive function and AD explained up to 1.1% of the variability in LASI-DAD cognitive domain scores. Our study represents an important stepping stone toward better characterization of the genetic architecture of cognitive aging in the Indian/South Asian population and highlights the need for further research that may lead to the identification of new variants unique to this population.

Investigating the potential impact of PCSK9-inhibitors on mood disorders using eQTL-based Mendelian randomization.

Prescription of PCSK9-inhibitors has increased in recent years but not much is known about its off-target effects. PCSK9-expression is evident in non-hepatic tissues, notably the brain, and genetic variation in the PCSK9 locus has recently been shown to be associated with mood disorder-related traits. We investigated whether PCSK9 inhibition, proxied by a genetic reduction in expression of PCSK9 mRNA, might have a causal adverse effect on mood disorder-related traits. We used genetic variants in the PCSK9 locus associated with reduced PCSK9 expression (eQTLs) in the European population from GTEx v8 and examined the effect on PCSK9 protein levels and three mood disorder-related traits (major depressive disorder, mood instability, and neuroticism), using summary statistics from the largest European ancestry genome-wide association studies. We conducted summary-based Mendelian randomization analyses to estimate the causal effects, and attempted replication using data from eQTLGen, Brain-eMETA, and the CAGE consortium. We found that genetically reduced PCSK9 gene-expression levels were significantly associated with reduced PCSK9 protein levels but not with increased risk of mood disorder-related traits. Further investigation of nearby genes demonstrated that reduced USP24 gene-expression levels was significantly associated with increased risk of mood instability (p-value range = 5.2x10-5-0.03), and neuroticism score (p-value range = 2.9x10-5-0.02), but not with PCSK9 protein levels. Our results suggest that genetic variation in this region acts on mood disorders through a PCSK9-independent pathway, and therefore PCSK9-inhibitors are unlikely to have an adverse impact on mood disorder-related traits.

Validation of Polygenic Risk Scores for Coronary Heart Disease in a Middle Eastern Cohort Using Whole Genome Sequencing.

Enthusiasm for using polygenic risk scores (PRSs) in clinical practice is tempered by concerns about their portability to diverse ancestry groups, thus motivating genome-wide association studies in non-European ancestry cohorts. We conducted a genome-wide association study for coronary heart disease in a Middle Eastern cohort using whole genome sequencing and assessed the performance of 6 PRSs developed with methods including LDpred (PGS000296), metaGRS (PGS000018), Pruning and Thresholding (PGS000337), and an EnsemblePRS we developed. Additionally, we evaluated the burden of rare variants in lipid genes in cases and controls. Whole genome sequencing at 30× coverage was performed in 1067 coronary heart disease cases (mean age=59 years; 70.3% males) and 6170 controls (mean age=40 years; 43.5% males). The majority of PRSs performed well; odds ratio (OR) per 1 SD increase (OR1sd) was highest for PGS000337 (OR1sd=1.81, 95% CI [1.66-1.98], P=3.07×10-41). EnsemblePRS performed better than individual PRSs (OR1sd=1.8, 95% CI [1.66-1.96], P=5.89×10-44). The OR for the 10th decile versus the remaining deciles was >3.2 for PGS000337, PGS000296, PGS000018, and reached 4.58 for EnsemblePRS. Of 400 known genome-wide significant loci, 33 replicated at P<10-4. However, the 9p21 locus did not replicate. Six suggestive (P<10-5) new loci/genes with plausible biological function were identified (eg, CORO7, RBM47, PDE4D). The burden of rare functional variants in LDLR, APOB, PCSK9, and ANGPTL4 was greater in cases than controls. Overall, we demonstrate that PRSs derived from European ancestry genome-wide association studies performed well in a Middle Eastern cohort, suggesting these could be used in the clinical setting while ancestry-specific PRSs are developed.

Abstract P049: Blood Pressure Polygenic Risk Score Stratifies Individuals With High Risk Of Hypertension In Different Ancestries

The heritability of arterial hypertension ranges from 25 to 68%, but the underlying genetic determinants remain elusive. Thousands of variants with small effects on systolic blood pressure (SBP) from European Ancestry Genome-Wide Association Studies have been used to derive genetic risk scores, whose predictive power in samples from diverse ancestries has yet to be determined. We used the LDPred2 algorithm and 423 thousand genetic variants from UK Biobank that were common to an admixed sample population from Brazil to derive SBP polygenic risk scores (PRS). We selected the best model that displayed a score with hyper-parameters ρ = 0.056, h 2 = 0.0739 and without sparsity, which presented the highest correlation coefficient with observed SBP (0.206) and SBP change per standard deviation increase (4.04mmHg) in a different set of data from the UK Biobank prior to test its predictive power on SBP and hypertension in a third set of the UK Biobank and two admixed Brazilian population samples. All three populations displayed similar normal distribution of PRS, with the UK Biobank PRS distribution slightly shifted to the right, presenting higher PRS average (7.8 vs. 5.6 and 6.4 in Baependi and Pelotas, respectively), but with similar standard deviation (3.3 vs. 3.2 for both Baependi and Pelotas). We used the PRS deciles to stratify the populations and observed a significant difference on SBP average between the top and bottom deciles in all three populations (14.43 mmHg, 9.34 mmHg and 7.51 mmHg for the UK Biobank, Baependi and Pelotas, respectively). We then compared the top 10% PRS versus the remaining 90% of the PRS distribution, and observed that high PRS is associated with 1.8, 2 to 3 and 3 to 4-fold increase in prehypertension, hypertension stage I and hypertension stage II risk, respectively, demonstrating that the increased risk is independently of age and ancestry. Considering the highly admixed nature of the Brazilian population, we provide evidence for the generalization of PRS between populations with different genetic structure.

The Relationship of Attention-Deficit/Hyperactivity Disorder With Posttraumatic Stress Disorder: A Two-Sample Mendelian Randomization and Population-Based Sibling Comparison Study

BackgroundAttention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship. MethodsLinkage disequilibrium score regression and 2-sample Mendelian randomization were used to test for genetic correlation (rg) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and 6 PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N = 2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons). ResultsADHD and PTSD had consistent rg (rg range, 0.43–0.52; p < .001). ADHD genetic liability was causally linked with increased risk for PTSD (β = 0.367; 95% CI, 0.186–0.552; p = 7.68 × 10−5). This result was not affected by heterogeneity, horizontal pleiotropy (Mendelian randomization Egger intercept = 4.34 × 10−4, p = .961), or other phenotypes and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio = 2.37; 95% CI, 1.98–3.53). ConclusionsOur findings add novel evidence supporting the need for early and effective treatment of ADHD, as patients with this diagnosis are at significantly higher risk to develop PTSD later in life.

505 Expanded GWAS meta-analysis offers novel insights into psoriasis biology

Genome-wide association studies (GWAS) play an important role in our understanding of psoriasis biology. We report an international effort (UK, USA, Canada, Germany, Norway, Estonia) to increase the power of psoriasis GWAS by meta-analysis of 18 case-control European-ancestry GWAS datasets (36,466 cases, 458,078 controls; cumulative effective sample size: 103,614). After stringent quality control, each dataset underwent genome-wide imputation. GWAS analyses were performed locally at collaborating centers, with standard-error weighted meta-analysis undertaken centrally.

Gene-based polygenic risk scores analysis of alcohol use disorder in African Americans

Genome-wide association studies (GWAS) in admixed populations such as African Americans (AA) have limited sample sizes, resulting in poor performance of polygenic risk scores (PRS). Based on the observations that many disease-causing genes are shared between AA and European ancestry (EA) populations, and some disease-causing variants are located within the boundaries of these genes, we proposed a novel gene-based PRS framework (PRSgene) by using variants located within disease-associated genes. Using the AA GWAS of alcohol use disorder (AUD) from the Million Veteran Program and the EA GWAS of problematic alcohol use as the discovery GWAS, we identified 858 variants from 410 genes that were AUD-related in both AA and EA. PRSgene calculated using these variants were significantly associated with AUD in three AA target datasets (P-values ranged from 7.61E−05 to 6.27E−03; Betas ranged from 0.15 to 0.21) and outperformed PRS calculated using all variants (P-values ranged from 7.28E−03 to 0.16; Betas ranged from 0.06 to 0.18). PRSgene were also associated with AUD in an EA target dataset (P-value = 0.02, Beta = 0.11). In AA, individuals in the highest PRSgene decile had an odds ratio of 1.76 (95% CI: 1.32–2.34) to develop AUD compared to those in the lowest decile. The 410 genes were enriched in 54 Gene Ontology biological processes, including ethanol oxidation and processes involving the synaptic system, which are known to be AUD-related. In addition, 26 genes were targets of drugs used to treat AUD or other diseases that might be considered for repurposing to treat AUD. Our study demonstrated that the gene-based PRS had improved performance in evaluating AUD risk in AA and provided new insight into AUD genetics.

METRO: Multi-ancestry transcriptome-wide association studies for powerful gene-trait association detection

Integrative analysis of genome-wide association studies (GWASs) and gene expression studies in the form of a transcriptome-wide association study (TWAS) has the potential to better elucidate the molecular mechanisms underlying disease etiology. Here we present a method, METRO, that can leverage gene expression data collected from multiple genetic ancestries to enhance TWASs. METRO incorporates expression prediction models constructed in different genetic ancestries through a likelihood-based inference framework, producing calibrated p values with substantially improved TWAS power. We illustrate the benefits of METRO in both simulations and applications to seven complex traits and diseases obtained from four GWASs. These GWASs include two of primarily European ancestry (n = 188,577 and 339,226) and two of primarily African ancestry (n = 42,752 and 23,827). In the real data applications, we leverage gene expression data measured on 1,032 African Americans and 801 European Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study to identify a substantially larger number of gene-trait associations as compared to existing TWAS approaches. The benefits of METRO are most prominent in applications to GWASs of African ancestry where the sample size is much smaller than GWASs of European ancestry and where a more powerful TWAS method is crucial. Among the identified associations are high-density lipoprotein-associated genes including PLTP and PPARG that are critical for maintaining lipid homeostasis and the type II diabetes-associated gene MAPT that supports microtubule-associated protein tau as a key component underlying impaired insulin secretion.

Polygenic risk score for general cognitive function is associated with measures of cognition in South Asians from the LASI-DAD Study.

Genome wide association studies (GWAS) conducted primarily in European Ancestry (EA) have identified hundreds of single nucleotide polymorphisms (SNPs) that are associated with general cognitive function. The association between these SNPs and cognitive function has not yet been evaluated in South Asians yet, either individually or in polygenic risk scores (PRS) which aggregate the effects from many SNPs across the genome. The goal of this study was to investigate whether SNPs identified in EA GWAS, either individually or as a PRS, were associated with a general cognitive factor and the Hindi version of the Mini-Mental State Examination (HMSE) score in 932 South Asians from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI-DAD). Participants were genotyped using the Illumina Global Screening Array and imputed to 1000G Phase 3v5. We used linear models to assess the association between 130 top SNPs from the EA GWAS (p<5e-08) and both measures of cognitive function after controlling for age, gender, and population structure. We also evaluated the association between PRSs using the top GWAS SNPs and the cognitive measures using the same models. Finally, we estimated the variation in cognitive function explained by the cognitive function PRS, Alzheimer's disease (AD) PRSs, and/or APOE e2 and e4 genotypes individually or simultaneously. Preliminary analyses showed that none of the GWAS SNPs were significantly associated either of the cognitive measures after multiple testing correction. The PRS, however, was significantly associated with the general cognitive factor and HMSE score (p<0.025). The PRS explained 0.40% and 0.59% of the variance in the general cognitive factor and HMSE score, and explained 1.50% and 1.85% of the variance when coupled with AD PRSs and APOE genotypes. SNPs identified for cognitive function in EA GWAS may not be as strongly associated in South Asians. However, the genetic risk score for both general cognitive function and AD contribute additively to cognitive function in LASI-DAD participants. Future large scale GWAS of general cognitive function and AD are needed to identify specific risk variants for cognition in South Asians.

Common and rare variants in topologically associated domains for cognitive function in South Asians from the LASI-DAD Study.

Genome-wide association studies (GWAS) in European ancestry (EA) participants have identified many loci associated with cognitive function. However, the association between variants at these loci and cognition has not been evaluated in South Asians. Due to ancestral genetic heterogeneity, the functional SNPs/variants in South Asians may be different than those identified in EA GWAS, even if the same genes/genomic regions are associated. Topologically associated domains (TADs), a basic unit of chromosome foldin, reflect a high level of intradomain interaction. This study used a region-based approach to investigate whether the TAD regions tagged by SNPs identified in EA GWAS were associated with a general cognitive factor and the Hindi version of the Mini-Mental State Examination (HMSE) score in 932 South Asians from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI-DAD). Participants were genotyped using the Illumina Global Screening Array and imputed to 1000G Phase 3v5. The sequence kernel association test (SKAT and SKAT-O) was used to assess the joint effects of multiple SNPs/variants in 146 TAD regions after controlling for age, gender, and population structure, with or without education. We used two weighting schemes: equal weight for all SNPs/variants (beta(1,1)), and upweighting of rare variants (beta(1,25)). Due to the large size of each TAD region, we used a moving window approach (window size: 300 variants). Three windows (in TAD region tagged by rs6819372) were significantly associated with the general cognitive factor using the equal SNP/variant weighting approach (FDR<0.1). Using the rare variant weighting approach, five windows (in TAD regions tagged by rs889956, rs7494275, and rs830386) were significantly associated with the general cognitive factor after adjusting for education. Those windows, however, often do not overlap with the SNPs identified from EA GWAS. Given that the associated regions often do not contain the EA GWAS SNPs GWAS, there may be substantial genetic heterogeneity between EA and South Asians even when the same gene regions are associated with cognition. Future work is needed to identify the specific variants that influence cognitive function in South Asians.

Does Maternal Normal Range Thyroid Function Play a Role in Offspring Birth Weight? Evidence From a Mendelian Randomization Analysis.

BackgroundThe association between normal range thyroid function and offspring birth weight has been postulated, but evidence from observational studies is prone to be confounded. We conducted a two-sample Mendelian randomization (MR) study to explore the causal effects of maternal thyroid stimulating hormone (TSH) and free thyroxine (FT4) on birth weight.MethodsWe utilized public shared summary-level statistics from European-ancestry genome wide association studies. We obtained 40 and 21 single nucleotide polymorphisms as instrumental variables, which were associated with TSH and FT4 levels at genome-wide significance (P < 5 × 10−8). Partitioned maternal effects on birth weight were retrieved from datasets contributed by the Early Growth Genetics Consortium. Inverse-variance weighted method was employed in the primary MR analysis and multiple sensitivity analyses were implemented.ResultsGenetically determined normal range thyroid function was not causally associated with offspring birth weight. Each one standard deviation (SD) increase in maternal TSH was associated with 0.002 SD higher of birth weight (95% confidence interval [CI], −0.021 to 0.025; P = 0.87). Similarly, change in birth weight was −0.001 SD (95% CI, −0.031 to 0.029; P = 0.94) per one SD higher in maternal FT4. Consistent results were yielded via additional MR methods. Sensitivity analyses demonstrated no presence of horizontal pleiotropy or heterogeneity.ConclusionThis MR study did not identify a causality between normal range thyroid function and offspring birth weight in the Europeans.

Abstract 2324: Replication and genetic risk score analysis for pancreatic cancer in a diverse multiethnic population

Abstract Background: Pancreatic cancer is one of the most fatal cancers, and it is projected to be the second leading cause of cancer-related death by 2030. Genome-wide association studies (GWAS) conducted in populations of European, Japanese, and Chinese-ancestry have identified several single nucleotide polymorphisms (SNPs) associated with pancreatic cancer risk. No studies yet have attempted to replicate these SNPs in African Americans, Latinos, or Native Hawaiians. In this study, we aimed to replicate the associations of 31 GWAS-identified SNPs with pancreatic cancer and build and test a polygenic risk score (PRS) for pancreatic cancer in an ethnically diverse population. Methods: We evaluated 31 risk variants in a nested case control study within the Multiethnic Cohort (MEC) and the Southern Community Cohort Study (SCCS). We included 692 pancreatic ductal adenocarcinoma (PDAC) cases and 13,777 controls from African-American (230 cases/5,235 controls), white (132 cases/570 controls), Japanese-American (182 cases/3,284 controls), Latino (105 cases/ 2,935 controls), and Native Hawaiian (43 cases/1,753 controls) participants. We first tested the association between each SNP and PDAC in a combined sample and by race/ethnicity. We then established a PRS using the 31 SNPs and log-odds weights from the combined sample results and tested the association between the score and PDAC risk. Results: Eleven of the 31 SNPs were replicated in the combined sample, ten initially discovered in GWAS of European ancestry and one in Japanese ancestry. Of these 11, three were also replicated in African Americans, two in whites, one in Japanese Americans, and one in Latinos at p&amp;lt;0.05. Additionally, we observed directional consistency of associations for 26 of 29 SNPs with minor allele frequency &amp;gt;0.05 in the multiethnic sample. The PRS showed strong performance in the multiethnic sample, with the top quintile (80%-100%) for the risk score associated with an odds ratio of 2.27 (95% CI: 1.73, 2.99) for PDAC compared with the middle quintile. Notably, the PRS was associated with PDAC risk within each racial/ethnic group (OR for continuous PRS ranged from 1.27 in Native Hawaiians to 1.97 in African Americans; P heterogeneity=0.16). Conclusion: This is the first study to test GWAS-identified risk variants associated with pancreatic cancer in a multiethnic population including high-risk African Americans, Japanese Americans and Latinos. We successfully replicated 11 of the 31 risk variants in the combined sample. PRS performance was high in majority of racial/ethnic groups. Our results suggest a potential utility of PRS with GWAS-identified risk variants for the identification of individuals at increased risk for PDAC across multiple ethnic groups. Citation Format: David Bogumil, David Conti, Xin Sheng, Lucy Xia, Xiao-ou Shu, Stephen Pandol, William Blot, Wei Zheng, Loic Le Marchand, Christopher Haiman, Veronica Wendy Setiawan. Replication and genetic risk score analysis for pancreatic cancer in a diverse multiethnic population [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2324.

Genomewide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy.

Microtubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genomewide association studies (GWAS) from two clinical cohorts treated with MTAs (Cancer and Leukemia Group B (CALGB) 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n=469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n=855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR1 ; e.g., rs74497159, βCALGB 40101 per allele log hazard ratio (95% confidence interval (CI))=0.591 (0.254-0.928), βCALGB 40502 per allele log hazard ratio (95% CI)=0.693 (0.334-1.053); PMETA =3.62×10-7 ) were the most highly ranked associations based on P values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in induced pluripotent stem cell-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.