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Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms

Molecular Psychiatry volume 17, pages 818–826 (2012)Cite this article

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Abstract

Because of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. Although microsatellite markers spaced every 10 cM typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carried out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 single-nucleotide polymorphisms. Of the ∼1100 families, 972 were informative for further analyses, and mean information content was 0.86 after pruning for linkage disequilibrium. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with bipolar II disorder (BPII) and 702 subjects with recurrent major depression. Three affection status models (ASMs) were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus recurrent major depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (non-parametric pairs LOD 3.4 for rs1046943 at 119 cM) and 9q21 (non-parametric pairs logarithm of odds (LOD) 3.4 for rs722642 at 78 cM) using only BPI and schizoaffective (SA), BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis, we observed 59 parametric LODs of 2 or greater, many of which are likely to be close to maximum possible scores. Although some linkage findings may be false positives, the results could help prioritize the search for rare variants using whole exome or genome sequencing.

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Acknowledgements

This work was supported by National Institutes of Health (NIH/NIMH) research Grant R01-MH077314 (JAB, WB). Wellcome Trust 045267/Z/WRE/MB/JAT (MG, RS).

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Authors and Affiliations

  1. Department of Psychiatry, University of Chicago, Chicago, IL, USA

    J A Badner, C-Y Liu & E S Gershon

  2. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    D Koller, T Foroud & H Edenberg

  3. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    H Edenberg

  4. Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA

    J I Nurnberger Jr

  5. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine and Bloomberg School of Public Health, Baltimore, MD, USA

    P P Zandi, V L Willour & J B Potash

  6. Department of Mental Health, Johns Hopkins University School of Medicine and Bloomberg School of Public Health, Baltimore, MD, USA

    P P Zandi

  7. Unit on the Genetic Basis of Mood and Anxiety Disorders, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, US Dept of Health and Human Services, Bethesda, MD, USA

    F J McMahon

  8. MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK

    M Hamshere, D Grozeva, E Green, G Kirov, I Jones & N Craddock

  9. Neuropharmacology & Neurobiology, University of Birmingham, Birmingham, UK

    L Jones

  10. Trinity College, Dublin, Ireland

    D Morris, R Segurado & M Gill

  11. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

    D Sadovnick

  12. Department of Psychiatry, St Paul's Hospital, Vancouver, BC, Canada

    R Remick

  13. Department of Psychiatry, University of Cincinnati, Cincinnati, OH, USA

    P Keck

  14. Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

    J Kelsoe

  15. School of Medicine and Health, University of Durham, Durham, UK

    M Ayub

  16. Division of Psychiatry, University of Edinburgh, Edinburgh, UK

    A MacLean & D Blackwood

  17. Department of Psychiatry, University of Utah Medical Center, Salt Lake City, UT, USA

    W McMahon, G J Lyon & R Robinson

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

    J Ross & W Byerley

  19. San Francisco Department of Veterans Affairs Medical Center, San Francisco, CA, USA

    W Byerley

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  1. J A Badner
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Correspondence to J A Badner or W Byerley.

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Badner, J., Koller, D., Foroud, T. et al. Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms. Mol Psychiatry 17, 818–826 (2012). https://doi.org/10.1038/mp.2011.89

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