Kardia, Sharon L.R.

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

P10 Coronary artery calcification (CAC), quantified by electron beam computed tomography, provides a measure of extent of coronary atherosclerosis in asymptomatic and symptomatic individuals. It is well recognized that coronary artery disease and CAC are complex processes that are influenced by many genetic and environmental factors. Several aspects of CAC quantity make genetic studies of it particularly challenging. These include the non-normality of CAC frequency distributions and the strong age- and sex-dependence of CAC levels. To search for regions that may contain genes influencing CAC quantity, a genome-wide scan was conducted on a sample enriched for hypertension from the Epidemiology of Coronary Artery Calcification Study. The genome-wide linkage scan was based on 370 anonymous markers spanning the 22 autosomal chromosomes in 29 families. The analysis sample consisted of 20 affected sib-pairs, 8 affected sib-trios and 1 family with 6 affected siblings. Here, affection status was defined as being above the 70th sex- and age-specific percentile based on a reference population. Mode-of-inheritance-free qualitative linkage analysis was used to analyze sib-pair data. Maximum multipoint lod scores were calculated using the computer software Genehunter-2. Weighted analyses were conducted using Holmans “possible triangle” constraint. The overall maximum lod scores were observed on chromosomes 6 (lod=2.22) and 10 (lod=3.24). Additional lod scores greater than 1.0 were observed on chromosomes 2, 14, 15 and 17. These results identify regions that may harbor genes involved in high sex- and age-specific levels of CAC (supported by HL46292).

Abstract —Results of genome-wide linkage analyses to identify chromosomal regions that influence interindividual variation in plasma lipid and apolipoprotein levels in the Rochester, Minn, population are reported. Analyses were conducted for total cholesterol (total-C), triglycerides (TGs), high density lipoprotein cholesterol (HDL-C), apolipoprotein A-I, apolipoprotein A-II, apolipoprotein B, apolipoprotein C-II, apolipoprotein C-III, apolipoprotein E, the total-C/HDL-C ratio, and the TG/HDL-C ratio. Genotypes were measured for 373 genome-wide marker loci on 1484 individuals distributed among 232 multigeneration pedigrees sampled without regard to health status. LOD scores and estimates of additive genetic variance associated with map locations were obtained by using the variance-component method of linkage analysis. No evidence of linkage with genes influencing variation in age served as a negative control. Plasma apolipoprotein E levels and the apolipoprotein E gene served as a positive control (LOD score 4.20). Evidence (LOD score >2.00) was provided that was suggestive of a gene or genes on chromosomes 4 and 5 influencing variation in the apolipoprotein A-II level, on chromosome 12 influencing variation in the apolipoprotein A-I level, and on chromosome 17 influencing variation of total-C/HDL-C. These analyses provide new information about genomic regions in humans that influence interindividual variation in plasma lipid and apolipoprotein levels and serve as a basis for further fine-mapping studies to identify new genes involved in lipid metabolism.

Abstract— Coronary artery disease (CAD) is the leading cause of mortality in the developed world. Although several CAD risk factors, including measures of lipid metabolism, obesity, and blood pressure, have a genetic basis, many genes for CAD susceptibility have yet to be identified. Coronary atherosclerosis is the major cause of CAD, but many with coronary atherosclerosis lack symptoms. Thus, a major limitation of using symptomatic CAD endpoints (eg, sudden coronary death, myocardial infarction) as a study outcome is substantial disease misclassification. Coronary artery calcification (CAC) is part of the atherosclerotic process and is an independent predictor of CAD endpoints. In the present study, CAC was noninvasively quantified by electron beam computed tomography. We performed genome-wide multipoint mode-of-inheritance-free linkage analysis on affected sib pairs, defined as being ≥ the 70th sex- and age-specific percentile for CAC quantity, in a sample of 29 families enriched for hypertension. Almost 95% of participants were asymptomatic for CAD. Our LOD score (log 10 odds in favor of linkage) results provide evidence that chromosomal regions 6p21.3 (maximum LOD score=2.22, P =0.00070) and 10q21.3 (maximum LOD score=3.24, P =0.000057) may harbor genes associated with subclinical coronary atherosclerosis.