Leveraging pleiotropy to discover and interpret GWAS results for sleep-associated traits

Akle, Sebastian; Chun, Sung; Teodosiadis, Athanasios; Cade, Brian E.; Wang, Heming; Sofer, Tamar; Evans, Daniel S.; Stone, Katie L.; Gharib, Sina A.; Mukherjee, Sutapa; Palmer, Lyle J.; Hillman, David R.; Rotter, Jerome I.; Stamatoyannopoulos, J; Redline, Susan; Cotsapas, Chris; Sunyaev, Shamil

doi:10.1101/832162

Cited by 4 publications

(1 citation statement)

References 106 publications

(171 reference statements)

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“…[58] Although we were unable to assess the genetic overlap between HbA1c, cholesterol, triglycerides in our study, methods appropriate in leveraging pleiotropy in larger studies have been developed. [59,60] These methods may enhance both discovery and genetic associations while creating potentially more powerful PRS for each of the traits. [13] Lastly, our study has several other limitations and strengths.…”

Section: Discussionmentioning

confidence: 99%

Associations of cardiometabolic polygenic risk scores with cardiovascular disease in African Americans

Workalemahu,

Ying,

et al. 2023

Preprint

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Background: Cardiovascular disease (CVD) is a complex disease, and genetic factors contribute individually or cumulatively to CVD risk. While African American women and men are disproportionately affected by CVD, their lack of representation in genomic investigations may widen disparities in health. We investigated the associations of cardiometabolic polygenic risk scores (PRSs) with CVD risk in African Americans. Methods: We used the Jackson Heart Study, a prospective cohort study of CVD in African American adults and the predicted atherosclerotic cardiovascular disease (ASCVD) 10-year risk. We included 40-79 years old adults without a history of coronary heart disease (CHD) or stroke at baseline. We derived genome-wide PRSs for systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, LDL cholesterol, hemoglobin A1c (HbA1c), triglycerides, and C-reactive protein (CRP) separately for each of the participants, using African-origin UK Biobank participants’ genome-wide association summary statistics. We estimated the associations between PRSs and 10-year predicted ASCVD risk adjusting for age, sex, study visit date, and genetic ancestry using linear and logistic regression models. Results: Participants (n=2,077) were 63% female and 66% never-smokers. They had mean (SD) 56 (10) years of age, 127.8 (16.3) mmHg SBP, 76.3 (8.7) mmHg DBP, 200.4 (40.2) mg/dL total cholesterol, 51.7 (14.7) mg/dL HDL cholesterol, 127.2 (36.7) mg/dL LDL cholesterol, 6.0 (1.3) mmol/mol HbA1c, 108.9 (81.7) mg/dL triglycerides and 0.53 (1.1) CRP. Their median (interquartile range) predicted 10-year predicted ASCVD risk was 8.0 (4.0-15.0). Participants in the >75th percentile for HbA1c PRS had 1.42 percentage-point greater predicted 10-year ASCVD risk (1.42 [95% CI: 0.58-2.26]) and higher odds of ≥10% predicted 10-year ASCVD risk (OR: 1.46 [95% CI: 1.03-2.07]) compared with those in the <25th percentile for HbA1c PRS. Participants in the >75th percentile for SBP PRS had higher odds of ≥10% predicted 10-year ASCVD risk (OR: 1.52 [95% CI: 1.07-2.15]) compared with those in the <25th percentile for SBP PRS. Conclusion: Among 40-79 years old African Americans without CHD and stroke, higher PRSs for HbA1c and SBP were associated with CVD risk. PRSs may help stratify individuals based on their clinical risk factors for CVD early prevention and clinical management.

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Section: Discussionmentioning

confidence: 99%

Associations of cardiometabolic polygenic risk scores with cardiovascular disease in African Americans

Workalemahu,

Ying,

et al. 2023

Preprint

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A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood

Kurniansyah

Goodman²,

Kelly³

et al. 2022

Nat Commun

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In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called “PRSsum”, forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type 2 diabetes, and chronic kidney disease.

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Shared associations identify causal relationships between gene expression and immune cell phenotypes

et al. 2021

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Genetic mapping studies have identified thousands of associations between common variants and hundreds of human traits. Translating these associations into mechanisms is complicated by two factors: they fall into gene regulatory regions; and they are rarely mapped to one causal variant. One way around these limitations is to find groups of traits that share associations, using this genetic link to infer a biological connection. Here, we assess how many trait associations in the same locus are due to the same genetic variant, and thus shared; and if these shared associations are due to causal relationships between traits. We find that only a subset of traits share associations, with many due to causal relationships rather than pleiotropy. We therefore suggest that simply observing overlapping associations at a genetic locus is insufficient to infer causality; direct evidence of shared associations is required to support mechanistic hypotheses in genetic studies of complex traits.

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Leveraging pleiotropy to discover and interpret GWAS results for sleep-associated traits

Cited by 4 publications

References 106 publications

Associations of cardiometabolic polygenic risk scores with cardiovascular disease in African Americans

Associations of cardiometabolic polygenic risk scores with cardiovascular disease in African Americans

A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood

Shared associations identify causal relationships between gene expression and immune cell phenotypes

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