Justice, Anne E.

ABSTRACT Obstructive sleep apnea (OSA) is a common, heritable disorder with diverse clinical presentations and etiologies. We conducted a genome-wide association meta-analysis of 492,107 individuals, including 46,028 OSA cases, identifying 14 genome-wide significant loci, eight of which are novel. Analyses adjusting for body mass index (BMI) revealed three loci independent of obesity, implicating alternative biological pathways contributing to disease. Integrative functional analyses, including chromatin interaction mapping, fine-mapping, and eQTL colocalization, prioritized candidate effector genes. Notably, implicated genes in chondrocytes were associated with craniofacial morphology in both mouse and human multivariate genotype-phenotype mapping, supporting a role for craniofacial structure in OSA risk. These findings highlight key genetic pathways (obesity-related, neurological, and craniofacial) underlying the development of OSA, offering new insights into its complex etiology.

Background: Lp(a) (lipoprotein [a]) levels are higher in individuals of African ancestry (AA) than in individuals of European ancestry (EA). We examined associations of genetically predicted Lp(a) levels with (1) atherosclerotic cardiovascular disease subtypes: coronary heart disease, cerebrovascular disease, peripheral artery disease, and abdominal aortic aneurysm and (2) nonatherosclerotic cardiovascular disease phenotypes, stratified by ancestry. Methods: We performed (1) Mendelian randomization analyses for previously reported cardiovascular associations and (2) Mendelian randomization–phenome-wide association analyses for novel associations. Analyses were stratified by ancestry in electronic Medical Records and Genomics, United Kingdom Biobank, and Million Veteran Program cohorts separately and in a combined cohort of 804 507 EA and 103 580 AA participants. Results: In Mendelian randomization analyses using the combined cohort, a 1-SD genetic increase in Lp(a) level was associated with atherosclerotic cardiovascular disease subtypes in EA—odds ratio and 95% CI for coronary heart disease 1.28 (1.16–1.41); cerebrovascular disease 1.14 (1.07–1.21); peripheral artery disease 1.22 (1.11–1.34); abdominal aortic aneurysm 1.28 (1.17–1.40); in AA, the effect estimate was lower than in EA and nonsignificant for coronary heart disease 1.11 (0.99–1.24) and cerebrovascular disease 1.06 (0.99–1.14) but similar for peripheral artery disease 1.16 (1.01–1.33) and abdominal aortic aneurysm 1.34 (1.11–1.62). In EA, a 1-SD genetic increase in Lp(a) level was associated with aortic valve disorders 1.34 (1.10–1.62), mitral valve disorders 1.18 (1.09–1.27), congestive heart failure 1.12 (1.05–1.19), and chronic kidney disease 1.07 (1.01–1.14). In AA, no significant associations were noted for aortic valve disorders 1.08 (0.94–1.25), mitral valve disorders 1.02 (0.89–1.16), congestive heart failure 1.02 (0.95–1.10), or chronic kidney disease 1.05 (0.99–1.12). Mendelian randomization–phenome-wide association analyses identified novel associations in EA with arterial thromboembolic disease, nonaortic aneurysmal disease, atrial fibrillation, cardiac conduction disorders, and hypertension. Conclusions: Many cardiovascular associations of genetically increased Lp(a) that were significant in EA were not significant in AA. Lp(a) was associated with atherosclerotic cardiovascular disease in four major arterial beds in EA but only with peripheral artery disease and abdominal aortic aneurysm in AA. Additionally, novel cardiovascular associations were detected in EA.

Background: The pathophysiology of lipoprotein (a) [Lp(a)] remains obscure. We conducted a phenome wide analysis study (PheWAS) to identify pleiotropic effects of LPA variants. Methods: Among 51,843 European-ancestry participants (age 58±16 years, 54% female) of the electronic MEdical Records and Genomics (eMERGE) network we assessed whether LPA variants exhibited pleiotropic affects through an electronic health record-based PheWAS. We adjusted significant associations by presence of atherosclerotic cardiovascular disease (ASCVD; defined as a composite of coronary heart disease, cerebrovascular disease, and peripheral artery disease) to determine whether those associations were independent of ASCVD. Results: In PheWAS analysis, we tested 864 phecodes with 36 independent LPA variants. We identified 21 significant associations with non-ASCVD phenotypes including heart failure, aortic valve stenosis, and chronic kidney disease of which 14 were replicated across independent cohorts. The strength of associations between the LPA variant rs10455872 and both heart failure and aortic valve stenosis related phecodes were significantly attenuated after adjustment for ASCVD. However, the association with chronic kidney disease phecode remained independent following adjustment for ASCVD without any attenuation in the estimated odds ratio (Table). Conclusions: LPA genetic variants were associated with aortic valve stenosis, heart failure and chronic kidney disease. The observed association of LPA variant rs10455872 with aortic stenosis and heart failure appear to be partially mediated by ASCVD, while the association with chronic kidney disease appears to be independent of ASCVD. Additional studies are needed to elucidate potential mechanisms by which Lp(a) may contribute to the pathogenesis of non-ASCVD disease phenotypes.

Abstract Background Across complex traits, common variants explain only a modest amount of variance, with SNP-heritability consistently below heritability estimates from close relatives. Here, we examined the contribution of rare variant to tobacco use risk in up to 26,000 individuals of European ancestry in the Trans-Omics for Precision Medicine (TOPMed) program with whole genome sequence (WGS;~30X coverage).Method We grouped about 35 million genetic variants by their minor allele frequencies (MAF) and linkage disequilibrium (LD) and estimated SNP-heritability for age of smoking initiation (N = 14,747), cigarettes smoked per day (N = 15,425), smoking cessation (N = 17,871) and initiation (N = 26,340) using linear mixed model. Rare variant population structure is detected and adjusted for by permutation procedure. We estimated an upper bound for narrow-sense heritability for tobacco use using available pedigrees consisting of close relatives in TOPMed.Results Rare variants with MAF 0.1–0.01%, mostly from non-protein altering region, accounted for 26% of variation in age of initiation and 15% for cessation. Follow-up analysis indicated that about one-third of these rare variants contribtion is potentially confounded with rare variants structure even after adjusting for principal components. After further conservative adjustment of population structure, we estimated SNP-based heritability to be 0.21 (SE = 0.08) for age of initiation, 0.15 (0.06) for cigarettes per day, 0.21 (0.09) for cessation, and 0.24 (0.07) for initiation, 1.8–4.5 times higher than previous SNP-based estimates. Our pedigree-based upper-bound for SNP-based heritability ranged from 0.18–0.35.Conclusion The substantial contribution of rare variants for several smoking phenotypes sheds light on the missing heritability and genetic etiology of tobacco use. It also informs fine-mapping strategies since the majority of the rare variant contribution was located in non-coding regulatory regions.

Abstract Background: High body mass index (BMI) is consistently linked to increased risk of colorectal cancer for men, whereas the association is less clear for women. As risk estimates from observational studies may be biased and/or confounded, we conducted a Mendelian randomization study to estimate the causal association between BMI and colorectal cancer. Methods: We used data from 10,226 colorectal cancer cases and 10,286 controls of European ancestry. The Mendelian randomization analysis used a weighted genetic risk score, derived from 77 genome-wide association study–identified variants associated with higher BMI, as an instrumental variable (IV). We compared the IV odds ratio (IV-OR) with the OR obtained using a conventional covariate-adjusted analysis. Results: Individuals carrying greater numbers of BMI-increasing alleles had higher colorectal cancer risk [per weighted allele OR, 1.31; 95% confidence interval (CI), 1.10–1.57]. Our IV estimation results support the hypothesis that genetically influenced BMI is directly associated with risk for colorectal cancer (IV-OR per 5 kg/m2, 1.50; 95% CI, 1.13–2.01). In the sex-specific IV analyses higher BMI was associated with higher risk of colorectal cancer among women (IV-OR per 5 kg/m2, 1.82; 95% CI, 1.26–2.61). For men, genetically influenced BMI was not associated with colorectal cancer (IV-OR per 5 kg/m2, 1.18; 95% CI, 0.73–1.92). Conclusions: High BMI was associated with increased colorectal cancer risk for women. Whether abdominal obesity, rather than overall obesity, is a more important risk factor for men requires further investigation. Impact: Overall, conventional epidemiologic and Mendelian randomization studies suggest a strong association between obesity and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(7); 1024–31. ©2015 AACR.