Genome-wide association study of suicide attempts in mood disorder patients

Perlis, Roy H., Huang, Jie, Purcell, Shaun, Fava, Maurizio, Rush, A. John, Sullivan, Patrick F., Hamilton, Steven P., McMahon, Francis J., Schulze, Thomas, Potash, James B., Zandi, Peter P., Willour, Virginia L., Penninx, Brenda W., Boomsma, Dorret I., Vogelzangs, Nicole, Middeldorp, Christel M., Rietschel, Marcella, Nothen, Markus, Cichon, Sven, Gurling, Hugh, Bass, Nick, McQuillin, Andrew, Hamshere, Marian Lindsay ORCID: https://orcid.org/0000-0002-8990-0958, Craddock, Nicholas John ORCID: https://orcid.org/0000-0003-2171-0610, Sklar, Pamela and Smoller, Jordan W. 2010. Genome-wide association study of suicide attempts in mood disorder patients. American Journal of Psychiatry 167 (12) , pp. 1499-1507. 10.1176/appi.ajp.2010.10040541

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Abstract

Objective: Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts. Method: The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort. Results: Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety. Conclusions: The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation. Epidemiologic studies indicate that mood disorders are associated with a marked increase in risk for suicide and suicide attempts, with one such study suggesting a 20-fold greater risk of death from suicide compared with the general population (1). The familiality of suicide risk is well-established (for a review, see Brodsky et al. [2]) and not accounted for solely by familial transmission of mood disorders (3—5). For example, a family-based study of a large, bipolar disorder cohort suggested that lifetime suicide attempts were among the more strongly familial features of the disorder (6). That risk for suicide attempt in particular is heritable is supported by twin studies (7, 8), with heritability estimates ranging from 30%—50%, intermediate between major depressive disorder and bipolar disorder. Adoption studies suggest that this risk cannot be explained solely by shared environment (9). Individual candidate-gene studies have implicated genes of the serotonergic or noradrenergic system (10—14), hypothalamic-pituitary-adrenal axis (15, 16), renin-angiotensin system (17), and neuronal development (1820) and function (21) in the propensity for suicide, using a variety of case and control definitions (for a review, see Brezo et al. [22]). However, given the limited understanding of pathophysiology, prioritizing candidates for study has been difficult and likely accounts for the near absence of consistent replication. The emergence of low-cost approaches for characterizing common genetic variation across the genome facilitates an alternate approach, which may lead to identification of truly novel risk factors, as has been the case in nonpsychiatric disorders (23). Therefore, we analyzed data from multiple genome-wide association studies to identify variations associated with suicide risk. To minimize the potential heterogeneity introduced by pooling mood disorder subjects, cohorts with bipolar disorder and major depression were examined separately and then combined for meta-analysis. In all, data from >8,700 mood disorder subjects were used to detect and replicate associations.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > R Medicine (General) R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Publisher:	American Psychiatric Publishing
ISSN:	0002-953X
Last Modified:	20 Oct 2022 08:31
URI:	https://orca.cardiff.ac.uk/id/eprint/28669

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