Age is the dominant risk factor for most chronic human diseases; yet the mechanisms by which aging confers this risk are largely unknown. 1 Recently, the age-related acquisition of somatic mutations in regenerating hematopoietic stem cell populations leading to clonal expansion was associated with both hematologic cancer 2 – 4 and coronary heart disease 5 , a phenomenon termed ‘Clonal Hematopoiesis of Indeterminate Potential’ (CHIP). 6 Simultaneous germline and somatic whole genome sequence analysis now provides the opportunity to identify root causes of CHIP. Here, we analyze high-coverage whole genome sequences from 97,691 participants of diverse ancestries in the NHLBI TOPMed program and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid, and inflammatory traits specific to different CHIP genes. Association of a genome-wide set of germline genetic variants identified three genetic loci associated with CHIP status, including one locus at TET2 that was African ancestry specific. In silico -informed in vitro evaluation of the TET2 germline locus identified a causal variant that disrupts a TET2 distal enhancer resulting in increased hematopoietic stem cell self-renewal. Overall, we observe that germline genetic variation shapes hematopoietic stem cell function leading to CHIP through mechanisms that are both specific to clonal hematopoiesis and shared mechanisms leading to somatic mutations across tissues.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, nineteen associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biologic pathways.

We conducted a meta-analysis of genome-wide association studies of systolic (SBP) and diastolic (DBP) blood pressure in 19,608 subjects of East Asian ancestry from the AGEN-BP consortium followed by de novo genotypingin 2 stages of replication involving 10,518 and 20,247 East Asian samples. We identified novel genome-wide significant (P < 5 × 10−8) associations between SBP or DBP and variants at four novel loci: ST7L-CAPZA1, FIGN-GRB14, ENPEP, and NPR3, as well as a novel variant near TBX3. Except for NPR3, all novel findings were significantly replicated for SBP or DBP in independent samples. Sevenloci previously reported in populations of European descent were confirmed. On 12q24.13, we observed an ethnic specific association(implicating rs671 at the ALDH2 locus as the causal variant) that affected SBP, DBP and multiple traits related to coronary artery disease. These findings provide novel insights into blood pressure regulation and potential targets for intervention.

These results highlight the importance of considering genetic factors in studies of risk factors for cardiovascular disease.

Obesity is a major predisposing factor for the development of several chronic diseases including non-insulin dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD). Leptin is a serum protein which is secreted by adipocytes and thought to play a role in the regulation of body fat. Leptin levels in humans have been found to be highly correlated with an individual's total adiposity. We performed a genome-wide scan and conducted multipoint linkage analysis using a general pedigree-based variance component approach to identify genes with measurable effects on quantitative variation in leptin levels in Mexican Americans. A microsatellite polymorphism, D2S1788, mapped to chromosome 2p21 (approximately 74 cM from the tip of the short arm) and showed strong evidence of linkage with serum leptin levels with a lod score of 4.95 (P = 9 x 10(-7)). This locus accounted for 47% of the variation in serum leptin levels, with a residual additive genetic component contributing an additional 24%. This region contains several potential candidate genes for obesity, including glucokinase regulatory protein (GCKR) and pro-opiomelanocortin (POMC). Our results show strong evidence of linkage of this region of chromosome 2 with serum leptin levels and indicate that this region could contain an important human obesity gene.