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[Preprint]. 2025 Feb 19:2024.12.27.24319111.

doi: 10.1101/2024.12.27.24319111.

Whole genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia

Runjia Li^{1

2

3}, Sarah A Gagliano Taliun^{4

5

6

7

3

8}, Kevin Liao^{4

9}, Matthew Flickinger⁴, Janet L Sobell¹⁰, Giulio Genovese¹¹, Adam E Locke^{4

12}, Rebeca Rothwell Chiu⁴, Jonathon LeFaive⁴, Jiongming Wang⁴, Taylor Martins^{4

13}, Sinéad Chapman¹¹, Anna Neumann¹¹, Robert E Handsaker^{11

14}, Donna K Arnett¹⁵, Kathleen C Barnes¹⁶, Eric Boerwinkle¹⁷, David Braff^{18

19}, Brian E Cade²⁰, Myriam Fornage²¹, Richard A Gibbs²², Karin F Hoth²³, Lifang Hou²⁴, Charles Kooperberg²⁵, Ruth J F Loos²⁶, Ginger A Metcalf²², Courtney G Montgomery²⁷, Alanna C Morrison¹⁷, Zhaohui S Qin²⁸, Susan Redline²⁰, Alexander P Reiner²⁹, Stephen S Rich³⁰, Jerome I Rotter³¹, Kent D Taylor³¹, Karine A Viaud-Martinez³²; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Genomic Psychiatry Cohort investigators; Tim B Bigdeli^{33

34

35}, Stacey Gabriel³⁶, Sebastian Zollner⁴, Albert V Smith⁴, Goncalo Abecasis^{4

12}, Steve McCarroll^{11

37}, Michele T Pato³⁸, Carlos N Pato³⁸, Michael Boehnke⁴, James Knowles³⁹, Hyun Min Kang⁴, Roel A Ophoff^{40

8}, Jason Ernst^{2

41

42

8}, Laura J Scott^{4

8}

Affiliations

¹ Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA, USA.
² Department of Biological Chemistry, University of California, Los Angeles, CA, USA.
³ These authors contributed equally: Runjia Li, Sarah A. Gagliano Taliun.
⁴ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
⁵ Department of Neurosciences, Université de Montréal, Montreal, Quebec, Canada.
⁶ Department of Medicine, Université de Montréal, Montreal, Quebec, Canada.
⁷ Montreal Heart Institute Research Centre, Montreal, Quebec, Canada.
⁸ Senior authors.
⁹ Genomics plc, Oxford, UK.
¹⁰ Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹¹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹² Regeneron Genetics Center, Tarrytown, NY, USA.
¹³ Arizona Department of Health Services, Phoenix, AZ, USA.
¹⁴ Department of Gentics, Harvard Medical School, Boston, MA, USA.
¹⁵ Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA.
¹⁶ Departments of Medicine & Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹⁷ Department of Epidemiology, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA.
¹⁸ Department of Psychiatry, University of California, San Diego, CA, USA.
¹⁹ VA San Diego Healthcare System, San Diego, CA, USA.
²⁰ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
²¹ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
²² Baylor College of Medicine Human Genome Sequencing Center, Department of Molecular and Human Genetics, Houston, TX, USA.
²³ Department of Psychiatry, University of Iowa, Iowa City, IA, USA.
²⁴ Department of Preventive Medicine, Northwestern University, Chicago, IL, USA.
²⁵ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
²⁶ Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁷ Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
²⁸ Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA, USA.
²⁹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
³⁰ Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA.
³¹ 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.
³² Illumina Laboratory Services, Illumina Inc., 5200 Illumina Way, San Diego, CA, USA.
³³ Institute for Genomics in Health (IGH), SUNY Downstate Health Sciences University, Brooklyn, NY, USA.
³⁴ Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA.
³⁵ VA New York Harbor Healthcare System, Brooklyn, NY, USA.
³⁶ Genomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³⁷ Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, NRB 260, Boston, MA, USA.
³⁸ Department of Psychiatry, Rutgers University, New Brunswick, NJ, USA.
³⁹ Human Genetics Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA.
⁴⁰ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
⁴¹ Department of Computational Medicine, University of California, Los Angeles, CA, USA.
⁴² Computer Science Department, University of California, Los Angeles, CA, USA.

PMID: 39763555
PMCID: PMC11703280
DOI: 10.1101/2024.12.27.24319111

Whole genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia

Runjia Li et al. medRxiv. 2025.

[Preprint]. 2025 Feb 19:2024.12.27.24319111.

doi: 10.1101/2024.12.27.24319111.

Authors

Affiliations

¹ Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA, USA.
² Department of Biological Chemistry, University of California, Los Angeles, CA, USA.
³ These authors contributed equally: Runjia Li, Sarah A. Gagliano Taliun.
⁴ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
⁵ Department of Neurosciences, Université de Montréal, Montreal, Quebec, Canada.
⁶ Department of Medicine, Université de Montréal, Montreal, Quebec, Canada.
⁷ Montreal Heart Institute Research Centre, Montreal, Quebec, Canada.
⁸ Senior authors.
⁹ Genomics plc, Oxford, UK.
¹⁰ Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹¹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹² Regeneron Genetics Center, Tarrytown, NY, USA.
¹³ Arizona Department of Health Services, Phoenix, AZ, USA.
¹⁴ Department of Gentics, Harvard Medical School, Boston, MA, USA.
¹⁵ Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA.
¹⁶ Departments of Medicine & Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹⁷ Department of Epidemiology, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA.
¹⁸ Department of Psychiatry, University of California, San Diego, CA, USA.
¹⁹ VA San Diego Healthcare System, San Diego, CA, USA.
²⁰ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
²¹ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
²² Baylor College of Medicine Human Genome Sequencing Center, Department of Molecular and Human Genetics, Houston, TX, USA.
²³ Department of Psychiatry, University of Iowa, Iowa City, IA, USA.
²⁴ Department of Preventive Medicine, Northwestern University, Chicago, IL, USA.
²⁵ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
²⁶ Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁷ Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
²⁸ Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA, USA.
²⁹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
³⁰ Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA.
³¹ 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.
³² Illumina Laboratory Services, Illumina Inc., 5200 Illumina Way, San Diego, CA, USA.
³³ Institute for Genomics in Health (IGH), SUNY Downstate Health Sciences University, Brooklyn, NY, USA.
³⁴ Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA.
³⁵ VA New York Harbor Healthcare System, Brooklyn, NY, USA.
³⁶ Genomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³⁷ Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, NRB 260, Boston, MA, USA.
³⁸ Department of Psychiatry, Rutgers University, New Brunswick, NJ, USA.
³⁹ Human Genetics Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA.
⁴⁰ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
⁴¹ Department of Computational Medicine, University of California, Los Angeles, CA, USA.
⁴² Computer Science Department, University of California, Los Angeles, CA, USA.

PMID: 39763555
PMCID: PMC11703280
DOI: 10.1101/2024.12.27.24319111

Update in

Whole-genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia.
Li R, Gagliano Taliun SA, Liao K, Flickinger M, Sobell JL, Genovese G, Locke AE, Chiu RR, LeFaive J, Wang J, Martins T, Chapman S, Neumann A, Handsaker RE, Arnett DK, Barnes KC, Boerwinkle E, Braff D, Cade BE, Fornage M, Gibbs RA, Hoth KF, Hou L, Kooperberg C, Loos RJF, Metcalf GA, Montgomery CG, Morrison AC, Qin ZS, Redline S, Reiner AP, Rich SS, Rotter JI, Taylor KD, Viaud-Martinez KA; National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Consortium; Genomic Psychiatry Cohort Investigators; Bigdeli TB, Gabriel S, Zollner S, Smith AV, Abecasis G, McCarroll SA, Pato MT, Pato CN, Boehnke M, Knowles J, Kang HM, Ophoff RA, Ernst J, Scott LJ. Li R, et al. HGG Adv. 2025 Aug 30;7(1):100499. doi: 10.1016/j.xhgg.2025.100499. Online ahead of print. HGG Adv. 2025. PMID: 40886051 Free PMC article.

Abstract

In studies of individuals of primarily European genetic ancestry, common and low-frequency variants and rare coding variants have been found to be associated with the risk of bipolar disorder (BD) and schizophrenia (SZ). However, less is known for individuals of other genetic ancestries or the role of rare non-coding variants in BD and SZ risk. We performed whole genome sequencing of African American individuals: 1,598 with BD, 3,295 with SZ, and 2,651 unaffected controls (InPSYght study). We increased power by incorporating 14,812 jointly called psychiatrically unscreened ancestry-matched controls from the Trans-Omics for Precision Medicine (TOPMed) Program for a total of 17,463 controls. To identify variants and sets of variants associated with BD and/or SZ, we performed single-variant tests, gene-based tests for singleton protein truncating variants, and rare and low-frequency variant annotation-based tests with conservation and universal chromatin states and sliding windows. We found suggestive evidence of BD association with single-variants on chromosome 18 and of lower BD risk associated with rare and low-frequency variants on chromosome 11 in a region with multiple BD GWAS loci, using a sliding window approach. We also found that chromatin and conservation state tests can be used to detect differential calling of variants in controls sequenced at different centers and to assess the effectiveness of sequencing metric covariate adjustments. Our findings reinforce the need for continued whole genome sequencing in additional samples of African American individuals and more comprehensive functional annotation of non-coding variants.

PubMed Disclaimer

Conflict of interest statement

Declaration of Interests A.E.L. is a shareholder of Regeneron Pharmaceuticals. K.C.B. is an employee of Oxford Nanopor Technologies Ltd. G.R.A. is a shareholder of Regeneron Pharmaceuticals.

Figures

**Figure 1.. Study overview**
(A) Number of total and of unrelated study participants for each case or control group; (B) Seven analysis groups: control/control and case/control; (C) Four analysis types (Total or Unrelated samples used in analysis); PTV: protein truncating variant

**Figure 2.**
Regional view of chromosome 18 locus showing evidence of association in the InPSYght BD versus InPSYght+TOPMed controls. Horizontal line shows genome-wide significance threshold of 5 x 10⁻⁹.

**Figure 3.**
Chromatin and conservation state burden test results for InPSYght cases versus InPSYght controls (A, B) and InPSYght cases versus InPSYght and TOPMed controls (C, D), with each point representing a ChromHMM or a ConsHMM state. Dashed lines show Bonferroni-based p-value thresholds (p=0.05/200). Diagonal lines show the unit slope. (A, C) QQ-plots with genomic inflation factors (λ) before and after inclusion of sequencing metadata PCs covariates. (B,D) Signed (by direction of enrichment coefficient) −log10 p-values before and after inclusion of sequencing metadata PCs covariates. Sign direction: Case enrichment values are positive, control enrichment values are negative.

**Figure 4.**
Test of repeat categories for enrichment of rare and low-frequency variants in TOPMed controls versus InPSYght controls, without (A, B) or with (C, D) sequencing metadata PCs covariates. “DNA?” represents elements with uncertain category classification to the DNA repeat element category. Horizontal dashed lines show Bonferroni-based p-value thresholds (p = 0.05/22). (A), (C): volcano plots with log odds ratio on the x-axis and −log10 p-values on the y-axis. (B), (D): Mean % of variants overlapping each repeat category on the x-axis (weighted by the minor allele frequencies, Methods), and −log10 p-values on the y-axis.

**Figure 5.**
WGScan genome-wide sliding window burden test for rare and low-frequency variants for InPSYght controls versus TOPMed controls. Horizontal lines show genome-wide p-value significance thresholds (p=2.18 x 10⁻⁸). Diagonal line shows the unit slope. (A, B) Manhattan plots of sliding window p-values without sequencing metadata PCs (A) and with sequencing metadata PCs (B). (C) QQ-plot for the window p-values, before and after inclusion of sequencing metadata PCs covariates. (D) Comparison between sliding window p-values before and after inclusion of sequencing metadata PCs covariates, showing windows in the chr5 region 58,500,010-58,550,007 (red).

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References

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This is a preprint.

Whole genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia

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Whole genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia

Authors

Affiliations

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Conflict of interest statement

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