title: Human Demographic History Impacts Genetic Risk Prediction across Diverse Populations.
abstract: The vast majority of genome-wide association studies (GWASs) are performed in Europeans, and their transferability to other populations is dependent on many factors (e.g., linkage disequilibrium, allele frequencies, genetic architecture). As medical genomics studies become increasingly large and diverse, gaining insights into population history and consequently the transferability of disease risk measurement is critical. Here, we disentangle recent population history in the widely used 1000 Genomes Project reference panel, with an emphasis on populations underrepresented in medical studies. To examine the transferability of single-ancestry GWASs, we used published summary statistics to calculate polygenic risk scores for eight well-studied phenotypes. We identify directional inconsistencies in all scores; for example, height is predicted to decrease with genetic distance from Europeans, despite robust anthropological evidence that West Africans are as tall as Europeans on average. To gain deeper quantitative insights into GWAS transferability, we developed a complex trait coalescent-based simulation framework considering effects of polygenicity, causal allele frequency divergence, and heritability. As expected, correlations between true and inferred risk are typically highest in the population from which summary statistics were derived. We demonstrate that scores inferred from European GWASs are biased by genetic drift in other populations even when choosing the same causal variants and that biases in any direction are possible and unpredictable. This work cautions that summarizing findings from large-scale GWASs may have limited portability to other populations using standard approaches and highlights the need for generalized risk prediction methods and the inclusion of more diverse individuals in medical genomics.
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Martin
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Gignoux
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Raymond K
authors.initials: RK
authors.lastname: Walters
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Genevieve L
authors.initials: GL
authors.lastname: Wojcik
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Neale
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 0G1, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Gravel
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Bustamante
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Center of Statistical Genetics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: eimear.kenny@mssm.edu.
authors.forename: Eimear E
authors.initials: EE
authors.lastname: Kenny
mesh_terms: D000569:Americas; D020022:Genetic Predisposition to Disease; D005826:Genetics, Medical; D005828:Genetics, Population; D006239:Haplotypes; D016045:Human Genome Project; D006801:Humans; D020412:Multifactorial Inheritance; D044469:Racial Groups / Q000235:genetics*
keywords: 1000 Genomes Project; GWAS; admixed populations; complex trait genetics; local ancestry; polygenic risk scores; population genetics; statistical genetics; summary statistics