Aggregate penetrance of genomic variants for actionable disorders in European and African Americans

Pradeep Natarajan^{1

2

3}, Nina B Gold^{2

4}, Alexander G Bick^{2

3

5}, Heather McLaughlin^{2

6

7}, Peter Kraft⁸, Heidi L Rehm^{2

6

7}, Gina M Peloso^{2

3}, James G Wilson⁹, Adolfo Correa¹⁰, Jonathan G Seidman^{2

5}, Christine E Seidman^{2

5

11

12}, Sekar Kathiresan^{1

2

3}, Robert C Green^{13

3

7

11}

Affiliations

¹ Center for Human Genetic Research, Cardiovascular Research Center, and Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
² Harvard Medical School, Boston, MA 02115, USA.
³ Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁴ Boston Children's Hospital, Boston, MA 02115, USA.
⁵ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁶ Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁷ Partners HealthCare Personalized Medicine, Boston, MA 02115, USA.
⁸ Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
⁹ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
¹⁰ Departments of Pediatrics and Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
¹¹ Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹² Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
¹³ Harvard Medical School, Boston, MA 02115, USA. rcgreen@bwh.harvard.edu.

PMID: 27831900
PMCID: PMC5823271
DOI: 10.1126/scitranslmed.aag2367

Aggregate penetrance of genomic variants for actionable disorders in European and African Americans

Pradeep Natarajan et al. Sci Transl Med. 2016.

. 2016 Nov 9;8(364):364ra151.

doi: 10.1126/scitranslmed.aag2367.

Authors

Affiliations

¹ Center for Human Genetic Research, Cardiovascular Research Center, and Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
² Harvard Medical School, Boston, MA 02115, USA.
³ Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁴ Boston Children's Hospital, Boston, MA 02115, USA.
⁵ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁶ Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁷ Partners HealthCare Personalized Medicine, Boston, MA 02115, USA.
⁸ Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
⁹ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
¹⁰ Departments of Pediatrics and Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
¹¹ Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹² Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
¹³ Harvard Medical School, Boston, MA 02115, USA. rcgreen@bwh.harvard.edu.

PMID: 27831900
PMCID: PMC5823271
DOI: 10.1126/scitranslmed.aag2367

Abstract

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.

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Conflict of interest statement

Competing interests: R.C.G. has equity in Genome Medical, a company that provides clinical genomics consultation services, and receives compensation for speaking or advisory services to AIA, Helix, Illumina, Invitae, and Prudential. S.K. has been a paid consultant to Regeneron, Celera, Bayer, Catabasis, Merck, Genomics PLC, San Therapeutics, Novartis, Sanofi, Alnylam, Eli Lilly, Leerink Partners, Noble Insights, and AstraZeneca. The remaining authors declare that they have no competing interests.

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Aggregate penetrance of genomic variants for actionable disorders in European and African Americans

Affiliations

Aggregate penetrance of genomic variants for actionable disorders in European and African Americans

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials