return of genomic results and aggregate penetrance in population-based cohorts

Conditions: Seemingly Healthy; Genetic Predisposition to Disease

Summary: the popseq project is a prospective cohort study that will develop and implement a genomic return of results (gror) process in the framingham heart study (fhs) and jackson heart study (jhs) cohorts and explore associated medical, behavioral, and economic outcomes. the study will interpret the genomic sequences of jhs/fhs participants previously sequenced by topmed who have consented to genomic return of results and/or genetic testing. we will develop and apply new methods for scalable screening/ classification of genomic variants and will explore genomic penetrance by phenotyping a subset of participants in the fhs and jhs.

the objectives of this project are to: 1) return clinically actionable genomic results to participants and track outcomes. among living fhs/jhs participants who have consented to gror, we will contact those in whom a detrimental actionable variant is discovered in one of the genes noted on the acmg recommended secondary findings list (estimate 2% of participants). 2) improve high-throughput methods for identifying valid pathogenic variation. refine and apply methods for high throughput screening of fhs/jhs genomes in a manner that retains high sensitivity for the detection of detrimental variants in \~3500 mendelian disease-associated genes while reducing the false discovery rate of variants that are not pathogenic/likely pathogenic. 3) explore aggregate penetrance for mendelian diseases. review phenotype data from a subset of fhs and jhs participants and compare this to genotypic data. data to be gathered include outcome and phenotypic data on the individuals who agree to gror and who learn that they have detrimental variant in one of the acmg listed genes. these data will be self-reported through surveys and available medical records will be reviewed. additional phenotypic data may be collected and reviewed for other non-actionable mendelian disease genes to explore genomic penetrance. research participants who are identified with a detrimental variant in an actionable gene may receive direct health benefits from learning this information; however, returning genomic results to healthy individuals not presenting for a medical indication may pose unexpected harms related to variant directed increases in screening and management. this study is focused on exploring the benefits and any potential harms related to returning genomic information in population-based cohorts. it will also allow us to better understand the penetrance of these variants in two populations not selected for disease status and will allow us to compare outcomes in a primarily african american population vs a caucasian population. developing methods to streamline variant analysis will help improve laboratory efficiency and will progress the field of variant curation and analysis.

Eligibility criteria:
inclusion criteria: * living individuals enrolled in the framingham heart study and the jackson heart study who have had their genomes sequenced as part of the topmed program. * adults over the age of 18 years * those who have consented to have their dna samples used for research purposes (and those who participate in gror who have consented to receive genomic information). exclusion criteria: * participants of the framingham heart study or jackson heart study who have not had their genomes sequenced as part of topmed * participants who did not opt for genomic/genetic research * participants who did/do not consent to receiving a genomic result (for the gror portion of this study only)