title: Genetic Diversity and Association Studies in US Hispanic/Latino Populations: Applications in the Hispanic Community Health Study/Study of Latinos.
abstract: US Hispanic/Latino individuals are diverse in genetic ancestry, culture, and environmental exposures. Here, we characterized and controlled for this diversity in genome-wide association studies (GWASs) for the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We simultaneously estimated population-structure principal components (PCs) robust to familial relatedness and pairwise kinship coefficients (KCs) robust to population structure, admixture, and Hardy-Weinberg departures. The PCs revealed substantial genetic differentiation within and among six self-identified background groups (Cuban, Dominican, Puerto Rican, Mexican, and Central and South American). To control for variation among groups, we developed a multi-dimensional clustering method to define a "genetic-analysis group" variable that retains many properties of self-identified background while achieving substantially greater genetic homogeneity within groups and including participants with non-specific self-identification. In GWASs of 22 biomedical traits, we used a linear mixed model (LMM) including pairwise empirical KCs to account for familial relatedness, PCs for ancestry, and genetic-analysis groups for additional group-associated effects. Including the genetic-analysis group as a covariate accounted for significant trait variation in 8 of 22 traits, even after we fit 20 PCs. Additionally, genetic-analysis groups had significant heterogeneity of residual variance for 20 of 22 traits, and modeling this heteroscedasticity within the LMM reduced genomic inflation for 19 traits. Furthermore, fitting an LMM that utilized a genetic-analysis group rather than a self-identified background group achieved higher power to detect previously reported associations. We expect that the methods applied here will be useful in other studies with multiple ethnic groups, admixture, and relatedness.
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA. Electronic address: mconomos@uw.edu.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Conomos
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Cecelia A
authors.initials: CA
authors.lastname: Laurie
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Stilp
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Gogarten
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Caitlin P
authors.initials: CP
authors.lastname: McHugh
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Nelson
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Tamar
authors.initials: T
authors.lastname: Sofer
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27514, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Fernández-Rhodes
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27514, USA.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Justice
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27514, USA.
authors.forename: Mariaelisa
authors.initials: M
authors.lastname: Graff
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27514, USA.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Young
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27514, USA.
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Seyerle
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27514, USA.
authors.forename: Christy L
authors.initials: CL
authors.lastname: Avery
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Graduate School of Public Health, San Diego State University, San Diego, CA 92182 USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Talavera
authors.affiliation: Institute for Minority Health, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Martha L
authors.initials: ML
authors.lastname: Daviglus
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Wassertheil-Smoller
authors.affiliation: Department of Psychology and Behavioral Medicine, University of Miami, Miami, FL 33124, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Schneiderman
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27514, USA.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Heiss
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Kaplan
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27514, USA.
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.affiliation: Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Alex P
authors.initials: AP
authors.lastname: Reiner
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Shaffer
authors.affiliation: Departments of Medicine and Epidemiology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: R Graham
authors.initials: RG
authors.lastname: Barr
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Kathleen F
authors.initials: KF
authors.lastname: Kerr
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Browning
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98077, USA.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Browning
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Weir
authors.affiliation: Division of Cardiovascular Sciences, NHLBI, NIH, Bethesda, MD 20892, USA.
authors.forename: M Larissa
authors.initials: ML
authors.lastname: Avilés-Santa
authors.affiliation: Division of Cardiovascular Sciences, NHLBI, NIH, Bethesda, MD 20892, USA.
authors.forename: George J
authors.initials: GJ
authors.lastname: Papanicolaou
authors.affiliation: Department of Statistics, University of Auckland, Auckland 1010, New Zealand.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lumley
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Szpiro
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27514, USA.
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Rice
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Thornton
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA. Electronic address: cclaurie@uw.edu.
authors.forename: Cathy C
authors.initials: CC
authors.lastname: Laurie
mesh_terms: D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006630:Hispanic or Latino / Q000235:genetics*; D006801:Humans; D014481:United States