Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendations

Roseann E Peterson¹, Karoline Kuchenbaecker², Raymond K Walters³, Chia-Yen Chen⁴, Alice B Popejoy⁵, Sathish Periyasamy⁶, Max Lam³, Conrad Iyegbe⁷, Rona J Strawbridge⁸, Leslie Brick⁹, Caitlin E Carey¹⁰, Alicia R Martin³, Jacquelyn L Meyers¹¹, Jinni Su¹², Junfang Chen¹³, Alexis C Edwards¹⁴, Allan Kalungi¹⁵, Nastassja Koen¹⁶, Lerato Majara¹⁷, Emanuel Schwarz¹³, Jordan W Smoller¹⁸, Eli A Stahl¹⁹, Patrick F Sullivan²⁰, Evangelos Vassos²¹, Bryan Mowry⁶, Miguel L Prieto²², Alfredo Cuellar-Barboza²³, Tim B Bigdeli¹¹, Howard J Edenberg²⁴, Hailiang Huang³, Laramie E Duncan²⁵

Affiliations

¹ Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: roseann.peterson@vcuhealth.org.
² Division of Psychiatry and UCL Genetics Institute, University College London, London W1T 7NF, UK.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA 94305, USA.
⁶ Queensland Brain Institute and Queensland Centre for Mental Health Research, The University of Queensland, Brisbane, QLD 4072, Australia.
⁷ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
⁸ Institute of Health and Wellbeing, University of Glasgow, Glasgow G12 8RZ, UK; Department of Medicine Solna, Karolinska Institute, Stockholm, SE 17176, Sweden.
⁹ Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University, Providence, RI 02906, USA.
¹⁰ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
¹¹ Department of Psychiatry, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA.
¹² Department of Psychology, Arizona State University, Tempe, AZ 85281, USA.
¹³ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany.
¹⁴ Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA 23298, USA.
¹⁵ Mental Health Section of MRC/UVRI and LSHTM Uganda Research Unit, P.O. Box 49, Entebbe, Uganda; Department of Psychiatry, Faculty of Medicine & Health Sciences, University of Stellenbosch, Cape Town, South Africa; Department of Medical Microbiology, College of Health Sciences, Makerere University, Kampala, Uganda; Global Initiative for Neuropsychiatric Genetics Education in Research, Harvard T.H. Chan School of Public Health and Broad Institute, Boston, MA 02115, USA.
¹⁶ Department of Psychiatry, Faculty of Medicine & Health Sciences, University of Stellenbosch, Cape Town, South Africa; Department of Medical Microbiology, College of Health Sciences, Makerere University, Kampala, Uganda; Global Initiative for Neuropsychiatric Genetics Education in Research, Harvard T.H. Chan School of Public Health and Broad Institute, Boston, MA 02115, USA.
¹⁷ Global Initiative for Neuropsychiatric Genetics Education in Research, Harvard T.H. Chan School of Public Health and Broad Institute, Boston, MA 02115, USA; MRC Human Genetics Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, 7925, South Africa.
¹⁸ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁹ Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
²⁰ Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SE 17176, Sweden; Genetics and Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²¹ Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, SE5 8AF, UK.
²² Department of Psychiatry, Faculty of Medicine, Universidad de los Andes, Santiago 7620001, Chile; Mental Health Service, Clínica Universidad de los Andes, Santiago 7620001, Chile; Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
²³ Department of Psychiatry, University Hospital and School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico; Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
²⁴ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
²⁵ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.

PMID: 31607513
PMCID: PMC6939869
DOI: 10.1016/j.cell.2019.08.051

Review

Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendations

Roseann E Peterson et al. Cell. 2019.

. 2019 Oct 17;179(3):589-603.

doi: 10.1016/j.cell.2019.08.051. Epub 2019 Oct 10.

Authors

Affiliations

¹ Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: roseann.peterson@vcuhealth.org.
² Division of Psychiatry and UCL Genetics Institute, University College London, London W1T 7NF, UK.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA 94305, USA.
⁶ Queensland Brain Institute and Queensland Centre for Mental Health Research, The University of Queensland, Brisbane, QLD 4072, Australia.
⁷ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
⁸ Institute of Health and Wellbeing, University of Glasgow, Glasgow G12 8RZ, UK; Department of Medicine Solna, Karolinska Institute, Stockholm, SE 17176, Sweden.
⁹ Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University, Providence, RI 02906, USA.
¹⁰ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
¹¹ Department of Psychiatry, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA.
¹² Department of Psychology, Arizona State University, Tempe, AZ 85281, USA.
¹³ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany.
¹⁴ Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA 23298, USA.
¹⁵ Mental Health Section of MRC/UVRI and LSHTM Uganda Research Unit, P.O. Box 49, Entebbe, Uganda; Department of Psychiatry, Faculty of Medicine & Health Sciences, University of Stellenbosch, Cape Town, South Africa; Department of Medical Microbiology, College of Health Sciences, Makerere University, Kampala, Uganda; Global Initiative for Neuropsychiatric Genetics Education in Research, Harvard T.H. Chan School of Public Health and Broad Institute, Boston, MA 02115, USA.
¹⁶ Department of Psychiatry, Faculty of Medicine & Health Sciences, University of Stellenbosch, Cape Town, South Africa; Department of Medical Microbiology, College of Health Sciences, Makerere University, Kampala, Uganda; Global Initiative for Neuropsychiatric Genetics Education in Research, Harvard T.H. Chan School of Public Health and Broad Institute, Boston, MA 02115, USA.
¹⁷ Global Initiative for Neuropsychiatric Genetics Education in Research, Harvard T.H. Chan School of Public Health and Broad Institute, Boston, MA 02115, USA; MRC Human Genetics Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, 7925, South Africa.
¹⁸ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁹ Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
²⁰ Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SE 17176, Sweden; Genetics and Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²¹ Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, SE5 8AF, UK.
²² Department of Psychiatry, Faculty of Medicine, Universidad de los Andes, Santiago 7620001, Chile; Mental Health Service, Clínica Universidad de los Andes, Santiago 7620001, Chile; Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
²³ Department of Psychiatry, University Hospital and School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico; Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
²⁴ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
²⁵ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.

PMID: 31607513
PMCID: PMC6939869
DOI: 10.1016/j.cell.2019.08.051

Abstract

Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development. Despite the perception that analyzing genetic data from diverse populations is difficult, it is scientifically and ethically imperative, and there is an expanding analytical toolbox to do it well.

Keywords: GWAS; admixed populations; ancestry; complex disease; cross-ancestry; diversity; population genetics; psychiatry; trans-ancestry; trans-ethnic.

PubMed Disclaimer

Figures

**Figure 1.. Diversity in GWAS of psychiatric disorders compared to global diversity.**
Participant numbers were extracted from the largest consortium publication(s) for each psychiatric disorder and are shown as fractions of the total sample size for each disorder. Note: Sample sizes are given in parentheses. Numbers reflect cases and controls combined. MD=major depression (490,999), SCZ=schizophrenia (205,661), PTSD=post-traumatic stress disorder (188,932), BIP=bipolar disorder (51,710), ADHD=attention deficit hyperactivity disorder (55,230), AUT=autism (46,350), AD=alcohol dependence (52,848), AN=anorexia (14,477). *For schizophrenia, the African American samples from an earlier publication (2009, International Schizophrenia Consortium) were not included in the most recent PGC schizophrenia publication (2014). Ancestry information for each participant was based on principal components analysis of genetic data. See Supplemental Table S1 for consortium studies and references.

**Figure 2:. Flow chart for quality control, imputation, and association analysis in diverse population samples.**
This flowchart depicts the general analysis framework for genome-wide association studies of participants with diverse ancestral backgrounds. Note: boxes with *red* headers indicate analyses done in samples with diverse ancestral backgrounds and *blue* denotes analysis done within samples in major population groups. The left path shows a strategy for the *stratified meta-analysis approach* and the right path shows steps for the *joint mixed model approach* [see Supplemental Table 2 for more detailed quality control (QC) considerations].

See this image and copyright information in PMC

References

1. Ahmad M, Sinha A, Ghosh S, Kumar V, Davila S, Yajnik CS, and Chandak GR (2017). Inclusion of Population-specific Reference Panel from India to the 1000 Genomes Phase 3 Panel Improves Imputation Accuracy. Sci. Rep 7, 6733. - PMC - PubMed
1. Akinhanmi MO, Biernacka JM, Strakowski SM, McElroy SL, Balls Berry JE, Merikangas KR, Assari S, McInnis MG, Schulze TG, LeBoyer M, et al. (2018). Racial disparities in bipolar disorder treatment and research: a call to action. Bipolar Disord. 20, 506–514. - PMC - PubMed
1. Banda Y, Kvale MN, Hoffmann TJ, Hesselson SE, Ranatunga D, Tang H, Sabatti C, Croen LA, Dispensa BP, Henderson M, et al. (2015). Characterizing Race/Ethnicity and Genetic Ancestry for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort. Genetics 200, 1285–1295. - PMC - PubMed
1. Barbeira AN, Dickinson SP, Bonazzola R, Zheng J, Wheeler HE, Torres JM, Torstenson ES, Shah KP, Garcia T, Edwards TL, et al. (2018). Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics. Nat. Commun 9, 1825. - PMC - PubMed
1. Barrett JC, and Cardon LR (2006). Evaluating coverage of genome-wide association studies. Nat. Genet 38, 659–662. - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendations

Affiliations

Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendations

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources