PR interval (PR) is a heritable electrocardiographic measure of atrial and atrioventricular nodal conduction. Changes in PR duration may be associated with atrial fibrillation, heart failure and ...all-cause mortality. Hispanic/Latino populations have high burdens of cardiovascular morbidity and mortality, are highly admixed and represent exceptional opportunities for novel locus identification. However, they remain chronically understudied. We present the first genome-wide association study (GWAS) of PR in 14 756 participants of Hispanic/Latino ancestry from three studies.
Study-specific summary results of the association between 1000 Genomes Phase 1 imputed single-nucleotide polymorphisms (SNPs) and PR assumed an additive genetic model and were adjusted for global ancestry, study centre/region and clinical covariates. Results were combined using fixed-effects, inverse variance weighted meta-analysis. Sequential conditional analyses were used to identify independent signals. Replication of novel loci was performed in populations of Asian, African and European descent. ENCODE and RoadMap data were used to annotate results.
We identified a novel genome-wide association (P<5×10
) with PR at
(rs6730558), which replicated in Asian and European populations (P<0.017). Additionally, we generalised 10 previously identified PR loci to Hispanics/Latinos. Bioinformatics annotation provided evidence for regulatory function in cardiac tissue. Further, for six loci that generalised, the Hispanic/Latino index SNP was genome-wide significant and identical to (or in high linkage disequilibrium with) the previously identified GWAS lead SNP.
Our results suggest that genetic determinants of PR are consistent across race/ethnicity, but extending studies to admixed populations can identify novel associations, underscoring the importance of conducting genetic studies in diverse populations.
Circulating white blood cell and platelet traits are clinically linked to various disease outcomes and differ across individuals and ancestry groups. Genetic factors play an important role in ...determining these traits and many loci have been identified. However, most of these findings were identified in populations of European ancestry (EA), with African Americans (AA), Hispanics/Latinos (HL), and other races/ethnicities being severely underrepresented.
We performed ancestry-combined and ancestry-specific genome-wide association studies (GWAS) for white blood cell and platelet traits in the ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) Study, including 16,201 AA, 21,347 HL, and 27,236 EA participants. We identified six novel findings at suggestive significance (P < 5E-8), which need confirmation, and independent signals at six previously established regions at genome-wide significance (P < 2E-9). We confirmed multiple previously reported genome-wide significant variants in the single variant association analysis and multiple genes using PrediXcan. Evaluation of loci reported from a Euro-centric GWAS indicated attenuation of effect estimates in AA and HL compared to EA populations.
Our results highlighted the potential to identify ancestry-specific and ancestry-agnostic variants in participants with diverse backgrounds and advocate for continued efforts in improving inclusion of racially/ethnically diverse populations in genetic association studies for complex traits.
Maternal smoking is associated with as much as a 50% reduced risk of preeclampsia, despite increasing risk of other poor pregnancy outcomes that often co-occur with preeclampsia, such as preterm ...birth and fetal growth restriction. Researchers have long sought to understand whether this perplexing association is biologically based, or a result of noncausal mechanisms. We examined whether smoking-response genes modify the smoking-preeclampsia association to investigate potential biological explanations.
We conducted a nested case-control study within the Norwegian Mother, Father and Child Birth Cohort (1999-2008) of 2,596 mother-child dyads. We used family-based log-linear Poisson regression to examine modification of the maternal smoking-preeclampsia relationship by maternal and fetal single nucleotide polymorphisms involved in cellular processes related to components of cigarette smoke (
= 1,915 with minor allele frequency ≥10%). We further investigated the influence of smoking cessation during pregnancy.
Three polymorphisms showed overall (
< 0.001) multiplicative interaction between smoking and maternal genotype. For rs3765692 (
) and rs10770343 (
), protection associated with smoking was reduced with two maternal copies of the risk allele and was stronger in continuers than quitters (interaction
= 0.02 for both loci, based on testing 3-level smoking by 3-level genotype). For rs2278361 (
) the inverse smoking-preeclampsia association was eliminated by the presence of a single risk allele, and again the trend was stronger in continuers than in quitters (interaction
= 0.01).
Evidence for gene-smoking interaction was limited, but differences by smoking cessation warrant further investigation. We demonstrate the potential utility of expanded dyad methods and gene-environment interaction analyses for outcomes with complex relationships between maternal and fetal genotypes and exposures.
· Maternal and fetal genotype may differentially influence preeclampsia.. · Smoking-related genes did not strongly modify smoking-preeclampsia association.. · Smoking cessation reduced strength of gene by smoking interactions..
Meta-analysis plays an important role in summarizing and synthesizing scientific evidence derived from multiple studies. With high-dimensional data, the incorporation of variable selection into ...meta-analysis improves model interpretation and prediction. Existing variable selection methods require direct access to raw data, which may not be available in practical situations. We propose a new approach, sparse meta-analysis (SMA), in which variable selection for meta-analysis is based solely on summary statistics and the effect sizes of each covariate are allowed to vary among studies. We show that the SMA enjoys the oracle property if the estimated covariance matrix of the parameter estimators from each study is available. We also show that our approach achieves selection consistency and estimation consistency even when summary statistics include only the variance estimators or no variance/covariance information at all. Simulation studies and applications to high-throughput genomics studies demonstrate the usefulness of our approach.
Aims/hypothesis
Type 2 diabetes is a growing global public health challenge. Investigating quantitative traits, including fasting glucose, fasting insulin and HbA
1c
, that serve as early markers of ...type 2 diabetes progression may lead to a deeper understanding of the genetic aetiology of type 2 diabetes development. Previous genome-wide association studies (GWAS) have identified over 500 loci associated with type 2 diabetes, glycaemic traits and insulin-related traits. However, most of these findings were based only on populations of European ancestry. To address this research gap, we examined the genetic basis of fasting glucose, fasting insulin and HbA
1c
in participants of the diverse Population Architecture using Genomics and Epidemiology (PAGE) Study.
Methods
We conducted a GWAS of fasting glucose (
n
= 52,267), fasting insulin (
n
= 48,395) and HbA
1c
(
n
= 23,357) in participants without diabetes from the diverse PAGE Study (23% self-reported African American, 46% Hispanic/Latino, 40% European, 4% Asian, 3% Native Hawaiian, 0.8% Native American), performing transethnic and population-specific GWAS meta-analyses, followed by fine-mapping to identify and characterise novel loci and independent secondary signals in known loci.
Results
Four novel associations were identified (
p
< 5 × 10
−9
), including three loci associated with fasting insulin, and a novel, low-frequency African American-specific locus associated with fasting glucose. Additionally, seven secondary signals were identified, including novel independent secondary signals for fasting glucose at the known
GCK
locus and for fasting insulin at the known
PPP1R3B
locus in transethnic meta-analysis.
Conclusions/interpretation
Our findings provide new insights into the genetic architecture of glycaemic traits and highlight the continued importance of conducting genetic studies in diverse populations.
Data availability
Full summary statistics from each of the population-specific and transethnic results are available at NHGRI-EBI GWAS catalog (
https://www.ebi.ac.uk/gwas/downloads/summary-statistics
).
Graphical abstract
A shared genetic susceptibility underlies diabetes, adiposity, and kidney phenotypes, yet few studies have leveraged this common genetic architecture in an attempt to clarify molecular functions, ...identify mechanistic common denominators, and prioritize variants for functional interrogation. We systematically interrogated evidence of a shared genetic architecture across adiposity (BMI N=90,813, waist circumferenceN=68,389, and waist to hip ratio WHR, N=63,747), type 2 diabetes (T2D, N=98,686, Ncase=26,440, fasting glucose FG, N=52,211, HbA1c N=23,357, and fasting insulin FI, N=48,395), and kidney (eGFR N=52,555 and chronic kidney disease CKD, N=91,382, Ncase=10,883) phenotypes in an ancestrally diverse study population (28% African American, 31% European ancestry, 28% Hispanic; 69% female; average age 56.9 (range 18-90)) within PAGE. We conducted a cross-trait meta-analysis using Adaptive Sum of Powered Score Tests (aSPU). We have identified 42 loci associated across these traits, (P<5e-8), including one preliminary novel cross-trait association for rs200812701, a nonsynonymous variant in KIF4B p.Ala491Val that was associated with BMI, waist circumference, and HbA1c. rs200812701 is rare (minor allele frequency MAF<0.1%) in all populations except Native Hawaiians (MAF=25%) and Asians (MAF=8%). Many of these loci are known for one trait, but the identification of shared genetic susceptibility for these loci is novel. For example, the PEPD locus is established for adiposity measures, namely WHR; however, this cross-trait association is driven more so by FI, T2D and eGFR. Our systematic interrogation of the shared genetic susceptibility underlying diabetes, adiposity, and kidney traits in an ancestrally diverse population has revealed novel loci and evidence of molecular functions and mechanistic common denominators underlying GWAS findings, demonstrating the utility of our approach.
Disclosure
H.M. Highland: None. C. Downie: None. S.F. Dimos: None. M. Graff: None. L.M. Polfus: None. B.F. Darst: None. A.R.M. Baldassari: None. C. Sitlani: None. A. Howard: None. C.L. Kooperberg: None. R. Loos: None. T. Matise: None. A.K. Mottl: None. K.E. North: None. C.L. Avery: Research Support; Self; Amgen.
Funding
American Diabetes Association (1-19-PDF-045 to H.M.M.); National Institutes of Health (T32HL007055, T32HL129982, R01HL142825)
Alcohol consumption is common in the United States and may confer beneficial cardiovascular effects at light-to-moderate doses. The alcohol-stroke relationship remains debated. We estimated the ...relationship between midlife, self-reported alcohol consumption and ischemic stroke and intracerebral hemorrhage (ICH) in a biracial cohort.
We examined 12,433 never and current drinkers in the Atherosclerosis Risk in Communities study, aged 45 to 64 years at baseline. Participants self-reported usual drinks per week of beer, wine, and liquor at baseline. We used multivariate Cox proportional hazards regression to assess the association of current alcohol consumption relative to lifetime abstention with incident ischemic stroke and ICH and modification by sex-race group. We modeled alcohol intake with quadratic splines to further assess dose-response relationships.
One third of participants self-reported abstention, 39% and 24%, respectively, consumed ≤3 and 4 to 17 drinks/wk, and only 5% reported heavier drinking. There were 773 ischemic strokes and 81 ICH over follow-up (median≈22.6 years). For ischemic stroke, light and moderate alcohol consumption were not associated with incidence (hazard ratios, 0.98; 95% CI, 0.79-1.21; 1.06, 0.84-1.34), whereas heavier drinking was associated with a 31% increased rate relative to abstention (hazard ratios, 1.31; 95% CI, 0.92-1.86). For ICH, moderate-to-heavy (hazard ratios, 1.99; 95% CI, 1.07-3.70), but not light, consumption increased incidence.
Self-reported light-to-moderate alcohol consumption at midlife was not associated with reduced stroke risk compared with abstention over 20 years of follow-up in the Atherosclerosis Risk in Communities study. Heavier consumption increased the risk for both outcomes as did moderate intake for ICH.
It is unclear whether testing for novel risk factors, such as a cardiovascular genetic risk score (cGRS), improves clinical decision making or health outcomes when used for targeting statin ...initiation in the primary prevention of atherosclerotic cardiovascular disease (ASCVD). Our objective was to estimate the cost-effectiveness of cGRS testing to inform clinical decision making about statin initiation in individuals with low-to-intermediate (2.5%-7.5%) 10-year predicted risk of ASCVD.
We evaluated the cost-effectiveness of testing for a 27-single-nucleotide polymorphism cGRS comparing 4 test/treat strategies: treat all, treat none, test/treat if cGRS is high, and test/treat if cGRS is intermediate or high. We tested a set of clinical scenarios of men and women, aged 45 to 65 years, with 10-year ASCVD risks between 2.5% and 7.5%. Our primary outcome measure was cost per quality-adjusted life-year gained. Under base case assumptions for statin disutility and cost, the preferred strategy is to treat all patients with ASCVD risk >2.5% without cGRS testing. For certain clinical scenarios, such as a 57-year-old man with a 10-year ASCVD risk of 7.5%, cGRS testing can be cost-effective under a limited set of assumptions; for example, when statins cost $15 per month and statin disutility is 0.013 (ie, willing to trade 3 months of life in perfect health to avoid 20 years of statin therapy), the preferred strategy (using a willingness-to-pay threshold of $50 000 per quality-adjusted life-year gained) is to test and treat if cGRS is intermediate or high. Overall, the results were not sensitive to assumptions about statin efficacy and harms.
Testing for a 27-single-nucleotide polymorphism cGRS is generally not a cost-effective approach for targeting statin therapy in the primary prevention of ASCVD for low- to intermediate-risk patients.
Mitigating age-related disease and disability presents challenges. Physical activity (PA) may be influential for prolonging health and functioning, warranting characterization of its patterns over ...the life course in population-based data. With the availability of up to three self-reported assessments of past year leisure-time PA (LTPA) over multiple decades in 15,036 participants (26% African American; 55% women; mean baseline age=54; median follow-up=23 years) from the Atherosclerosis Risk in Communities (ARIC) Study sampled from four U.S. communities, race-sex-stratified trajectories of average weekly intensity (metabolic equivalent of task (MET)), duration (hours), and energy expenditure or volume (MET-h) of LTPA were developed from age 45 to 90 using joint models to accommodate expected non-ignorable attrition. Declines in weekly LTPA intensity, duration, and volume from age 70 to 90 were observed in white women (2.9 to 1.2 MET; 2.5 to 0.6 h; 11.1 to 2.6 MET-h), white men (2.5 to 1.0 MET; 3.5 to 1.8 h; 15.5 to 6.4 MET-h), African American women (2.5 to 2.4 MET; 0.8 to 0.1 h; 6.7 to 6.0 MET-h), and African American men (2.3 to 1.4 MET; 1.5 to 0.6 h; 8.0 to 2.3 MET-h). These data reveal population-wide shifts towards less active lifestyles in older adulthood.
Concurrent variation in adiposity and inflammation suggests potential shared functional pathways and pleiotropic disease underpinning. Yet, exploration of pleiotropy in the context of ...adiposity-inflammation has been scarce, and none has included self-identified Hispanic/Latino populations. Given the high level of ancestral diversity in Hispanic American population, genetic studies may reveal variants that are infrequent/monomorphic in more homogeneous populations.
Using multi-trait Adaptive Sum of Powered Score (aSPU) method, we examined individual and shared genetic effects underlying inflammatory (CRP) and adiposity-related traits (Body Mass Index BMI), and central adiposity (Waist to Hip Ratio WHR) in HLA participating in the Population Architecture Using Genomics and Epidemiology (PAGE) cohort (N = 35,871) with replication of effects in the Cameron County Hispanic Cohort (CCHC) which consists of Mexican American individuals.
Of the > 16 million SNPs tested, variants representing 7 independent loci were found to illustrate significant association with multiple traits. Two out of 7 variants were replicated at statistically significant level in multi-trait analyses in CCHC. The lead variant on APOE (rs439401) and rs11208712 were found to harbor multi-trait associations with adiposity and inflammation.
Results from this study demonstrate the importance of considering pleiotropy for improving our understanding of the etiology of the various metabolic pathways that regulate cardiovascular disease development.
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