Correlations between complex human phenotypes vary by genetic background, gender, and environment

Michael Elgart; Matthew O Goodman; Carmen Isasi; Han Chen; Alanna C Morrison; Paul S de Vries; Huichun Xu; Ani W Manichaikul; Xiuqing Guo; Nora Franceschini; Bruce M Psaty; Stephen S Rich; Jerome I Rotter; Donald M Lloyd-Jones; Myriam Fornage; Adolfo Correa; Nancy L Heard-Costa; Ramachandran S Vasan; Ryan Hernandez; Robert C Kaplan; Susan Redline; Trans-Omics for Precision Medicine (TOPMed) Consortium; Tamar Sofer

doi:10.1016/j.xcrm.2022.100844

Correlations between complex human phenotypes vary by genetic background, gender, and environment

Cell Rep Med. 2022 Dec 20;3(12):100844. doi: 10.1016/j.xcrm.2022.100844. Epub 2022 Dec 12.

Authors

Michael Elgart¹, Matthew O Goodman², Carmen Isasi³, Han Chen⁴, Alanna C Morrison⁵, Paul S de Vries⁵, Huichun Xu⁶, Ani W Manichaikul⁷, Xiuqing Guo⁸, Nora Franceschini⁹, Bruce M Psaty¹⁰, Stephen S Rich¹¹, Jerome I Rotter⁸, Donald M Lloyd-Jones¹², Myriam Fornage¹³, Adolfo Correa¹⁴, Nancy L Heard-Costa¹⁵, Ramachandran S Vasan¹⁶, Ryan Hernandez¹⁷, Robert C Kaplan¹⁸, Susan Redline²; Trans-Omics for Precision Medicine (TOPMed) Consortium; Tamar Sofer¹⁹

Affiliations

¹ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. Electronic address: melgart@bwh.harvard.edu.
² Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
³ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
⁴ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA; Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁵ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁶ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
⁷ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁸ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁹ Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
¹⁰ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA.
¹¹ Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA.
¹² Department of Preventive Medicine, Northwestern University, Chicago, IL, USA.
¹³ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA; Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
¹⁴ Department of Population Health Science, University of Mississippi Medical Center, Jackson, MS, USA.
¹⁵ Boston University and National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
¹⁶ Boston University and National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA; Preventive Medicine & Epidemiology, and Cardiovascular Medicine, Medicine, Boston University School of Medicine, and Epidemiology, Boston University School of Public Health, Boston, MA, USA.
¹⁷ Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
¹⁸ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA; Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA, USA.
¹⁹ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address: tsofer@bwh.harvard.edu.

Abstract

We develop a closed-form Haseman-Elston estimator for genetic and environmental correlation coefficients between complex phenotypes, which we term HEc, that is as precise as GCTA yet ∼20× faster. We estimate genetic and environmental correlations between over 7,000 phenotype pairs in subgroups from the Trans-Omics in Precision Medicine (TOPMed) program. We demonstrate substantial differences in both heritabilities and genetic correlations for multiple phenotypes and phenotype pairs between individuals of self-reported Black, Hispanic/Latino, and White backgrounds. We similarly observe differences in many of the genetic and environmental correlations between genders. To estimate the contribution of genetics to the observed phenotypic correlation, we introduce "fractional genetic correlation" as the fraction of phenotypic correlation explained by genetics. Finally, we quantify the enrichment of correlations between phenotypic domains, each of which is comprised of multiple phenotypes. Altogether, we demonstrate that the observed correlations between complex human phenotypes depend on the genetic background of the individuals, their gender, and their environment.

Keywords: Haseman-Elston regression; Hispanic Community Health Study/Study of Latinos; Trans-Omics in Precision Medicine; admixed population; genetic architecture; genetic background; genetic correlation; heritability; household correlation; multi-ethnic.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Female
Genetic Background*
Humans
Male
Phenotype

Grants and funding

R21 HL145425/HL/NHLBI NIH HHS/United States