DESCRIPTION (provided by applicant): Hypertension (HTN) accounts for ~50% of cardiovascular morbidity and mortality, with huge consequences for individuals and society. Despite identifying 100 single nucleotide polymorphisms (SNPs) at 80 loci regulating inter-individual variation in blood pressure (BP) very little of its phenotypic variability has been explained (~1- 2%): nor has its biological pathogenesis, beyond gender, age, BMI and other covariate effects, been understood. This is in contrast to other cardiovascular risk factors such as blood lipids where ~40% of its variance has been explained in recognized biochemical pathways, through the investigation of, in part, much larger numbers of subjects. We propose here to use the unique features of the Kaiser Permanente RPGEH cohort to not only enhance gene discovery by adding >100,000 samples but specifically investigate the clinically important effects of the mapped genes on target organ damage, the clinical pathology induced by hypertension. We emphasize whole genome sequencing of phenotypic extremes from this multi-ethnic US cohort, systematic investigation of both rare and common genetic variation, the use of electronic health records to better define the BP phenotype and target organ damage and address the effect of medications, and, state-of-the-art statistical, computational and annotation analyses to achieve three goals: (1) Whole-genome sequencing (WGS) at blood pressure (BP) extremes to identify large-effect BP alleles in multiple ethnicities from a clinic-based cohort. (2 Identify the genomic contribution of variants to systolic (SBP) and diastolic (DBP) measures and hypertension (HTN) in a multi-ethnic cohort. (3) Construct a multi-locus genetic risk score associated with BP risk and TOD in the same individuals followed across time.

PUBLIC HEALTH RELEVANCE: Hypertension (HTN) accounts for ~50% of cardiovascular morbidity and mortality, with huge consequences for individuals and society. Despite identifying a part of its genetic basis we do not know how these genes impact target organ damage, the clinical pathology induced by HTN. This collaborative study will use whole genome sequencing of phenotypic extremes from the Kaiser Permanente multi-ethnic US cohort, consider both rare and common genetic variation, and use electronic health records to better define the BP phenotype and target organ damage.