Aggregate penetrance of genomic variants for actionable disorders in European and African Americans.
In populations that have not been selected for family history of disease, it is unclear how commonly pathogenic variants (PVs) in disease-associated genes for rare Mendelian conditions are found and how often they are associated with clinical features of these conditions. We conducted independent, prospective analyses of participants in two community-based epidemiological studies to test the hypothesis that persons carrying PVs in any of 56 genes that lead to 24 dominantly inherited, actionable conditions are more likely to exhibit the clinical features of the corresponding diseases than those without PVs. Among 462 European American Framingham Heart Study (FHS) and 3223 African-American Jackson Heart Study (JHS) participants who were exome-sequenced, we identified and classified 642 and 4429 unique variants, respectively, in these 56 genes while blinded to clinical data. In the same participants, we ascertained related clinical features from the participants' clinical history of cancer and most recent echocardiograms, electrocardiograms, and lipid measurements, without knowledge of variant classification. PVs were found in 5 FHS (1.1%) and 31 JHS (1.0%) participants. Carriers of PVs were more likely than expected, on the basis of incidence in noncarriers, to have related clinical features in both FHS (80.0% versus 12.4%) and JHS (26.9% versus 5.4%), yielding standardized incidence ratios of 6.4 [95% confidence interval (CI), 1.7 to 16.5; P = 7 × 10-4) in FHS and 4.7 (95% CI, 1.9 to 9.7; P = 3 × 10-4) in JHS. Individuals unselected for family history who carry PVs in 56 genes for actionable conditions have an increased aggregated risk of developing clinical features associated with the corresponding diseases.
Center for Human Genetic Research, Cardiovascular Research Center, and Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.|Harvard Medical School, Boston, MA 02115, USA.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Pradeep
P
Natarajan
Harvard Medical School, Boston, MA 02115, USA.|Boston Children's Hospital, Boston, MA 02115, USA.
Nina B
NB
Gold
Harvard Medical School, Boston, MA 02115, USA.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.|Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Alexander G
AG
Bick
Harvard Medical School, Boston, MA 02115, USA.|Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.|Partners HealthCare Personalized Medicine, Boston, MA 02115, USA.
Heather
H
McLaughlin
Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
Peter
P
Kraft
Harvard Medical School, Boston, MA 02115, USA.|Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.|Partners HealthCare Personalized Medicine, Boston, MA 02115, USA.
Heidi L
HL
Rehm
Harvard Medical School, Boston, MA 02115, USA.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Gina M
GM
Peloso
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
James G
JG
Wilson
Departments of Pediatrics and Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Adolfo
A
Correa
Harvard Medical School, Boston, MA 02115, USA.|Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Jonathan G
JG
Seidman
Harvard Medical School, Boston, MA 02115, USA.|Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.|Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.|Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
Christine E
CE
Seidman
Center for Human Genetic Research, Cardiovascular Research Center, and Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.|Harvard Medical School, Boston, MA 02115, USA.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Sekar
S
Kathiresan
Harvard Medical School, Boston, MA 02115, USA. rcgreen@bwh.harvard.edu.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.|Partners HealthCare Personalized Medicine, Boston, MA 02115, USA.|Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Robert C
RC
Green
D000328:Adult; D001741:Black or African American; D000368:Aged; D002318:Cardiovascular Diseases / Q000208:ethnology* / Q000235:genetics*; D059472:Exome; D005260:Female; D005500:Follow-Up Studies; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019683:Penetrance; D010641:Phenotype; D011446:Prospective Studies; D012307:Risk Factors; D014481:United States; D044465:White People