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Genome-wide mapping of brain phenotypes in extended pedigrees with strong genetic loading for bipolar disorder

Molecular Psychiatry volume 26, pages 5229–5238 (2021)Cite this article

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Abstract

Bipolar disorder is a highly heritable illness, associated with alterations of brain structure. As such, identification of genes influencing inter-individual differences in brain morphology may help elucidate the underlying pathophysiology of bipolar disorder (BP). To identify quantitative trait loci (QTL) that contribute to phenotypic variance of brain structure, structural neuroimages were acquired from family members (n = 527) of extended pedigrees heavily loaded for bipolar disorder ascertained from genetically isolated populations in Latin America. Genome-wide linkage and association analysis were conducted on the subset of heritable brain traits that showed significant evidence of association with bipolar disorder (n = 24) to map QTL influencing regional measures of brain volume and cortical thickness. Two chromosomal regions showed significant evidence of linkage; a QTL on chromosome 1p influencing corpus callosum volume and a region on chromosome 7p linked to cortical volume. Association analysis within the two QTLs identified three SNPs correlated with the brain measures.

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Fig. 1: Top linkage results for each of the 24 BP-associated brain phenotypes.
Fig. 2: Results of association testing within the two significant linkage regions.

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Acknowledgements

We wish to thank our late colleagues Lori Altshuler MD and George Bartzokis MD for their valuable input and guidance on this work.

Funding

This research was supported by National Institute of Health Grants R01MH075007, R01MH095454, P30NS062691; (NBF), K23MH074644-01; (CEB) R01HG006695; (CS), and K08MH086786 (SCF), the Joanne and George Miller Family Endowed Term Chair (CEB), and Colciencias and Codi-University of Antioquia (CL-J).

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Authors and Affiliations

  1. Department of Psychiatry and Biobehavioral Science, University of California, Los Angeles, CA, USA

    Scott C. Fears, Susan K. Service, Ileana Aldana, Terri M. Teshiba, Noor B. Al-Sharif, Maria Jalbrzikowski, Todd A. Tishler, Julio Molina, Rita M. Cantor, Nelson B. Freimer & Carrie E. Bearden

  2. Section of Mental Health, Greater Los Angeles Veterans Administration, Los Angeles, CA, USA

    Scott C. Fears

  3. Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA

    Scott C. Fears, Susan K. Service, Nelson B. Freimer & Carrie E. Bearden

  4. Department of Genetics, Evolution and Environment, University College London, London, WC1E 6BT, UK

    Barbara Kremeyer

  5. Cell and Molecular Biology Research Center, Universidad de Costa Rica, San Pedro de Montes de Oca, Costa Rica

    Carmen Araya, Xinia Araya, Julio Bejarano, Margarita Ramirez & Gabriel Macaya

  6. Insituto de Alta Tecnologìa Mèdica, Medellín, Colombia

    Gabriel Castrillón

  7. Department of Psychiatry, Harbor-UCLA Hospital, Los Angeles, CA, USA

    Juliana Gomez-Franco

  8. Grupo de Investigación en Psiquiatría (Research Group in Psychiatry (GIPSI)), Departamento de Psiquiatría, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia

    Maria C. Lopez, Gabriel Montoya, Patricia Montoya & Carlos Lopez-Jaramillo

  9. Department of Psychiatry and Family Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA

    Javier Escobar

  10. Ministry of Education Key Laboratory of Contemporary Anthropology and Collaborative Innovation Center of Genetics and Development, School of Life Sciences and Human Phenome Institute, Fudan University, Yangpu District, Shanghai, China

    Andrés Ruiz-Linares

  11. UMR 7268 ADES, CNRS, Aix-Marseille Université, EFS, Faculté de médecine Timone, Marseille, 13005, France

    Andrés Ruiz-Linares

  12. Department of Genetics, Evolution and Environment, and UCL Genetics Institute, University College London, London, WC1E 6BT, UK

    Andrés Ruiz-Linares

  13. BioCiencias Lab, Guatemala, Guatemala

    Julio Molina

  14. Department of Psychiatry, University of California, San Francisco, CA, USA

    Victor I. Reus

  15. Department of Human Genetics, University of California, Los Angeles, CA, USA

    Rita M. Cantor

  16. Department of Health Research and Policy, Stanford University, Stanford, CA, USA

    Chiara Sabatti

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Correspondence to Scott C. Fears.

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Fears, S.C., Service, S.K., Kremeyer, B. et al. Genome-wide mapping of brain phenotypes in extended pedigrees with strong genetic loading for bipolar disorder. Mol Psychiatry 26, 5229–5238 (2021). https://doi.org/10.1038/s41380-020-0805-6

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