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Genome-wide autozygosity is associated with lower general cognitive ability

Molecular Psychiatry volume 21, pages 837–843 (2016)Cite this article

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Abstract

Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity—multiple homozygous SNPs in a row—to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003–0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.

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Acknowledgements

We acknowledge Bruce Walsh, Ken Krauter and Brian Browning for their helpful comments and suggestions in the preparation of this manuscript. This work has been supported by grants from the National Institutes of Health: R01 MH079800 and P50 MH080173 to AKM. RC2 MH089964 to TL. R01 MH080912 to DCG K23 MH077807 to KEB. K01 MH085812 and R01 MH100141 to MCK. The LOGOS study was supported by the University of Crete Research Funds Account (E.L.K.E.1348). The TOP Study Group was supported by the Research Council of Norway grants 213837 and 223273, South-East Norway Health Authority grants 2013–123, and K.G. Jebsen Foundation. The NCNG study was supported by Research Council of Norway grants 154313/V50 and 177458/V50. The NCNG GWAS was financed by grants from the Bergen Research Foundation, the University of Bergen, the Research Council of Norway (FUGE, Psykisk Helse), Helse Vest RHF and Dr Einar Martens Fund.

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Authors and Affiliations

  1. Department of Medicine, Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    D P Howrigan & B M Neale

  2. Stanley Center for Psychiatric Genetics, Broad Institute of Harvard and MIT, Cambridge Center, Cambridge, MA, USA

    D P Howrigan & B M Neale

  3. Division of Data Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA

    M A Simonson

  4. Department of Psychology, University of Edinburgh, Edinburgh, UK

    G Davies & I J Deary

  5. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK

    S E Harris, J M Starr, D C Liewald, I J Deary & P M Visscher

  6. Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine and MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK

    S E Harris

  7. Institute of Genetics and Molecular Medicine, MRC Human Genetics Unit, Western General Hospital, University of Edinburgh, Edinburgh, UK

    A Tenesa

  8. The Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, UK

    A Tenesa

  9. Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK

    J M Starr

  10. Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia

    A McRae, M J Wright, G W Montgomery, N Hansell, N G Martin & P M Visscher

  11. Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia

    A McRae & P M Visscher

  12. Centre for Integrated Genomic Medical Research, Institute of Population Health, University of Manchester, Manchester, UK

    A Payton, W E Ollier & N Pendleton

  13. Centre for Clinical and Cognitive Neurosciences, Institute of Brain Behaviour and Mental Health, University of Manchester, Salford Royal NHS Foundation Trust, Salford, UK

    M Horan

  14. Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands

    A Abdellaoui & D I Boomsma

  15. Neuroscience Campus Amsterdam, Amsterdam, The Netherlands

    A Abdellaoui & D I Boomsma

  16. EMGO+ Institute for Health and Care Research, Amsterdam, The Netherlands

    D I Boomsma

  17. Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA

    P DeRosse, A K Malhotra & T Lencz

  18. Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA

    P DeRosse, A K Malhotra & T Lencz

  19. Departments of Psychiatry and Molecular Medicine, Hofstra North Shore – LIJ School of Medicine, Hempstead, NY, USA

    P DeRosse, A K Malhotra & T Lencz

  20. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    E E M Knowles & D C Glahn

  21. NORMENT, KG Jebsen Centre, Oslo, Norway

    S Djurovic, I Melle, O A Andreassen & K Sundet

  22. Oslo University Hospital, Oslo, Norway

    S Djurovic, I Melle & O A Andreassen

  23. University of Oslo, Oslo, Norway

    I Melle & O A Andreassen

  24. Department of Clinical Medicine, K.G. Jebsen Centre for Psychosis Research, Dr. Einar Martens Research Group for Biological Psychiatry, University of Bergen, Bergen, Norway

    A Christoforou, V M Steen & S L Hellard

  25. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway

    A Christoforou, V M Steen & S L Hellard

  26. Department of Psychology, University of Oslo, Oslo, Norway

    K Sundet, I Reinvang & T Espeseth

  27. Norwegian Center for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway

    T Espeseth

  28. K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway

    A J Lundervold

  29. Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway

    A J Lundervold

  30. Kavli Research Centre for Aging and Dementia, Haraldsplass Deaconess Hospital, Bergen, Norway

    A J Lundervold

  31. Department of Psychiatry, University of Halle, Halle, Germany

    I Giegling, B Konte, A M Hartmann & D Rujescu

  32. Department of Psychiatry, Department of Genetics and Genomic Sciences, Friedman Brain Institute, and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    P Roussos & K E Burdick

  33. James J. Peters VA Medical Center, Mental Illness Research Education and Clinical Center (MIRECC), Bronx, NY, USA

    P Roussos

  34. Department of Psychology, University of Crete, Rethymno, Crete, Greece

    S Giakoumaki

  35. Department of Psychiatry, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece

    P Bitsios

  36. Computational Medicine Laboratory, Institute of Computer Science at FORTH, Heraklion, Greece

    P Bitsios

  37. School of Psychology, National University of Ireland Galway, Galway, Ireland

    G Donohoe

  38. Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, CO, USA

    R P Corley & M C Keller

  39. University of Queensland Diamantina Institute, The University of Queensland, Princess Alexandra Hospital, Brisbane, QLD, Australia

    P M Visscher

  40. Department of Psychology, University of Colorado at Boulder, Boulder, CO, USA

    M C Keller

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  47. M C Keller
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Correspondence to D P Howrigan or M C Keller.

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Howrigan, D., Simonson, M., Davies, G. et al. Genome-wide autozygosity is associated with lower general cognitive ability. Mol Psychiatry 21, 837–843 (2016). https://doi.org/10.1038/mp.2015.120

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