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A genome-wide association study of attempted suicide

Molecular Psychiatry volume 17, pages 433–444 (2012)Cite this article

Abstract

The heritable component to attempted and completed suicide is partly related to psychiatric disorders and also partly independent of them. Although attempted suicide linkage regions have been identified on 2p11-12 and 6q25-26, there are likely many more such loci, the discovery of which will require a much higher resolution approach, such as the genome-wide association study (GWAS). With this in mind, we conducted an attempted suicide GWAS that compared the single-nucleotide polymorphism (SNP) genotypes of 1201 bipolar (BP) subjects with a history of suicide attempts to the genotypes of 1497 BP subjects without a history of suicide attempts. In all, 2507 SNPs with evidence for association at P<0.001 were identified. These associated SNPs were subsequently tested for association in a large and independent BP sample set. None of these SNPs were significantly associated in the replication sample after correcting for multiple testing, but the combined analysis of the two sample sets produced an association signal on 2p25 (rs300774) at the threshold of genome-wide significance (P=5.07 × 10−8). The associated SNPs on 2p25 fall in a large linkage disequilibrium block containing the ACP1 (acid phosphatase 1) gene, a gene whose expression is significantly elevated in BP subjects who have completed suicide. Furthermore, the ACP1 protein is a tyrosine phosphatase that influences Wnt signaling, a pathway regulated by lithium, making ACP1 a functional candidate for involvement in the phenotype. Larger GWAS sample sets will be required to confirm the signal on 2p25 and to identify additional genetic risk factors increasing susceptibility for attempted suicide.

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Acknowledgements

This work was supported by grants from the National Institute of Mental Health (MH079240 to VLW) and the American Foundation for Suicide Prevention (VLW). It was also supported in part by R01 MH079799 (JWS). Drs Willour and Potash were also supported by Margaret Price Investigatorships. DNA samples were prepared and distributed by Rutgers University under a contract from the NIMH. We are grateful to the many interviewers and diagnosticians who contributed to this project, and to the families who devoted their time and effort to the study. Genome-wide SNP genotyping of the NIMH samples was performed through the Genetic Association Information Network under the direction of The Bipolar Genome Study (BiGS) Consortium. The Principal Investigators and Co-Investigators were: University of California San Diego, La Jolla, CA: John R Kelsoe (PI), Tiffany A Greenwood, Thomas B Barrett, Caroline M Nievergelt, Rebecca McKinney, Paul D Shilling; Scripps Research Institute, La Jolla, CA: Nicholas Schork (PI), Erin N Smith, Cinnamon S Bloss; Indiana University, Bloomington, IN: John I Nurnberger, Jr (PI), Howard J Edenberg, Tatiana Foroud, Daniel M Koller; University of Chicago, Chicago, IL: Elliot Gershon (PI), Chunyu Liu, Judith A Badner; Rush University Medical Center, Chicago, IL: William A Scheftner; Howard University, Washington, DC: William B Lawson (PI), Evaristus A Nwulia, Maria Hipolito; University of Iowa, Iowa City, IA: William Coryell (PI); Washington University, St Louis, MO: John Rice (PI); University of California San Francisco, San Francisco, CA: William Byerley (PI); National Institute of Mental Health, Bethesda, MD: Francis McMahon (PI), Thomas G Schulze; University of Pennsylvania, Philadelphia, PA: Wade Berrettini (PI); Johns Hopkins University, Baltimore, MD: James B Potash (PI), Peter P Zandi, Pamela B Mahon; University of Michigan, Ann Arbor, MI: Melvin G McInnis (PI), Sebastian Zöllner, Peng Zhang; The Translational Genomics Research Institute, Phoenix, AZ: David Craig (PI), Szabolics Szelinger. Data and biomaterials were collected in four projects that participated in the National Institute of Mental Health (NIMH) Bipolar Disorder Genetics Initiative. From 1991 to 1998, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, U01 MH46282: John Nurnberger, Marvin Miller and Elizabeth Bowman; Washington University, St Louis, MO, U01 MH46280: Theodore Reich, Allison Goate and John Rice; Johns Hopkins University, Baltimore, MD U01 MH46274: J Raymond DePaulo, Jr, Sylvia Simpson and Colin Stine; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, MD: Elliot Gershon, Diane Kazuba and Elizabeth Maxwell. Data and biomaterials were collected as part of 10 projects that participated in the National Institute of Mental Health (NIMH) Bipolar Disorder Genetics Initiative. From 1999 to 2003, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, R01 MH59545: John Nurnberger, Marvin J Miller, Elizabeth S Bowman, N Leela Rau, P Ryan Moe, Nalini Samavedy, Rif El-Mallakh (at the University of Louisville), Husseini Manji (at the Wayne State University), Debra A Glitz (at the Wayne State University), Eric T Meyer, Carrie Smiley, Tatiana Foroud, Leah Flury, Danielle M Dick, Howard Edenberg; Washington University, St Louis, MO, R01 MH059534: John Rice, Theodore Reich, Allison Goate, Laura Bierut; Johns Hopkins University, Baltimore, MD, R01 MH59533: Melvin McInnis, J Raymond DePaulo, Jr, Dean F MacKinnon, Francis M Mondimore, James B Potash, Peter P Zandi, Dimitrios Avramopoulos and Jennifer Payne; University of Pennsylvania, PA, R01 MH59553: Wade Berrettini; University of California at Irvine, CA, R01 MH60068: William Byerley and Mark Vawter; University of Iowa, IA, R01 MH059548: William Coryell and Raymond Crowe; University of Chicago, IL, R01 MH59535: Elliot Gershon, Judith Badner, Francis McMahon, Chunyu Liu, Alan Sanders, Maria Caserta, Steven Dinwiddie, Tu Nguyen, Donna Harakal; University of California at San Diego, CA, R01 MH59567: John Kelsoe, Rebecca McKinney; Rush University, IL, R01 MH059556: William Scheftner, Howard M Kravitz, Diana Marta, Annette Vaughn-Brown and Laurie Bederow; NIMH Intramural Research Program, Bethesda, MD, 1Z01MH002810-01: Francis J McMahon, Layla Kassem, Sevilla Detera-Wadleigh, Lisa Austin and Dennis L Murphy. Data and biomaterials were collected as part of 11 projects (Study 40) that participated in the National Institute of Mental Health (NIMH) Bipolar Disorder Genetics Initiative. From 2003 to 2007, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, R01 MH59545: John Nurnberger, Marvin J Miller, Elizabeth S Bowman, N Leela Rau, P Ryan Moe, Nalini Samavedy, Rif El-Mallakh (at the University of Louisville), Husseini Manji (at Johnson and Johnson), Debra A Glitz (at the Wayne State University), Eric T Meyer (at the Oxford University, UK), Carrie Smiley, Tatiana Foroud, Leah Flury, Danielle M Dick (at the Virginia Commonwealth University), Howard Edenberg; Washington University, St Louis, MO, R01 MH059534: John Rice, Theodore Reich, Allison Goate, Laura Bierut K02 DA21237; Johns Hopkins University, Baltimore, MD, R01 MH59533: Melvin McInnis, J Raymond DePaulo, Jr, Dean F MacKinnon, Francis M Mondimore, James B Potash, Peter P Zandi, Dimitrios Avramopoulos and Jennifer Payne; University of Pennsylvania, PA, R01 MH59553: Wade Berrettini; University of California at San Francisco, CA, R01 MH60068: William Byerley and Sophia Vinogradov; University of Iowa, IA, R01 MH059548: William Coryell, and Raymond Crowe; University of Chicago, IL, R01 MH59535: Elliot Gershon, Judith Badner, Francis McMahon, Chunyu Liu, Alan Sanders, Maria Caserta, Steven Dinwiddie, Tu Nguyen, Donna Harakal; University of California at San Diego, CA, R01 MH59567: John Kelsoe, Rebecca McKinney; Rush University, IL, R01 MH059556: William Scheftner, Howard M Kravitz, Diana Marta, Annette Vaughn-Brown, and Laurie Bederow; NIMH Intramural Research Program, Bethesda, MD, 1Z01MH002810-01: Francis J McMahon, Layla Kassem, Sevilla Detera-Wadleigh, Lisa Austin, Dennis L Murphy; Howard University: William B Lawson, Evarista Nwulia, and Maria Hipolito.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

    V L Willour, F Seifuddin, P B Mahon, D Jancic, M Pirooznia, B Schweizer, F S Goes, F M Mondimore, D F MacKinnon, J R DePaulo Jr, P P Zandi & J B Potash

  2. US Department of Health and Human Services, Genetic Basis of Mood and Anxiety Disorders Unit, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD, USA

    J Steele, T G Schulze & F J McMahon

  3. Department of Psychiatry and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA

    R H Perlis, P H Lee, J Huang, S Purcell & J W Smoller

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

    J R Kelsoe & P D Shilling

  5. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany

    M Rietschel

  6. Department of Psychiatry, University of Bonn, Bonn, Germany

    M Rietschel

  7. Department of Genomics, Life & Brain Center and Institute of Human Genetics, University of Bonn, Bonn, Germany

    M Nöthen

  8. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany

    S Cichon

  9. Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany

    S Cichon

  10. Department of Mental Health Sciences, University College London, London, UK

    H Gurling

  11. Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, UK

    N Craddock

  12. Department of Psychiatry and Psychotherapy, Section on Psychiatric Genetics, Georg-August-Universität, Göttingen, Germany

    T G Schulze

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  1. V L Willour
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  2. F Seifuddin
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  3. P B Mahon
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  10. D F MacKinnon
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  11. R H Perlis
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  12. P H Lee
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  13. J Huang
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  14. J R Kelsoe
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  16. M Rietschel
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  17. M Nöthen
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  18. S Cichon
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  19. H Gurling
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  20. S Purcell
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  21. J W Smoller
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  22. N Craddock
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  23. J R DePaulo Jr
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  24. T G Schulze
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  25. F J McMahon
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  26. P P Zandi
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  27. J B Potash
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The Bipolar Genome Study (BiGS) Consortium

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Correspondence to V L Willour.

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The authors declare no conflict of interest. Dr Perlis has received consulting fees from Concordant Rater Systems, Proteus Biomedical, and RIDVentures, and royalties/patent fees from Concordant Rater Systems.

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Willour, V., Seifuddin, F., Mahon, P. et al. A genome-wide association study of attempted suicide. Mol Psychiatry 17, 433–444 (2012). https://doi.org/10.1038/mp.2011.4

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