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A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene for schizophrenia and bipolar disorder

Knight, H.M. and Pickard, B.S. and Maclean, Alan and Malloy, M.P. and Soares, D.C. and McRae, A.F. and Condie, A. and White, A. (2009) A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene for schizophrenia and bipolar disorder. American Journal of Human Genetics. ISSN 0002-9297

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Schizophrenia and bipolar disorder are leading causes of morbidity across all Populations, with heritability estimates of similar to 80% indicating a substantial genetic component. Population genetics and genome-wide association studies Suggest an overlap of genetic risk factors between these illnesses but it is unclear how this genetic component is divided between common gene polymorphisms, rare genomic copy number variants, and rare gene sequence mutations. We report evidence that the lipid transporter gene ABCA13 is a susceptibility factor for both schizophrenia and bipolar disorder. After the initial discovery of its disruption by a chromosome abnormality in a person with schizophrenia, we resequenced ABCA13 exons in 100 cases with schizophrenia and 100 controls. Multiple rare coding variants were identified including one nonsense and nine missense mutations and compound heterozygosity/homozygosity in six cases. Variants were genotyped in additional schizophrenia, bipolar, depression (n > 1600), and control (n > 950) cohorts and the frequency of all rare variants combined was greater than controls in schizophrenia (OR = 1.93, p = 0.0057) and bipolar disorder (OR = 2.71, p = 0.00007). The population attributable risk of these mutations was 2.2% for schizophrenia and 4.0% for bipolar disorder. In a Study of 21 families of mutation carriers, we genotyped affected and unaffected relatives and found significant linkage (LOD = 4.3) of rare variants with a phenotype including schizophrenia, bipolar disorder, and major depression. These data identify a candidate gene, highlight the genetic overlap between schizophrenia, bipolar disorder, and depression, and suggest that rare coding variants may contribute significantly to risk of these disorders.

Item type: Article
ID code: 25916
Notes: Strathprints' policy is to record up to 8 authors per publication, plus any additional authors based at the University of Strathclyde. More authors may be listed on the official publication than appear in the Strathprints' record.
Keywords: genome-wide association, postmortem orbitofrontal cortex, glutamate-receptor gene, fatty-acids, common diseases, atp hydrolysis, protein, transporter, prediction, family, Neuroscience. Biological psychiatry. Neuropsychiatry, Genetics, Genetics, Genetics(clinical)
Subjects: Medicine > Internal medicine > Neuroscience. Biological psychiatry. Neuropsychiatry
Science > Natural history > Genetics
Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
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    Depositing user: Strathprints Administrator
    Date Deposited: 25 Aug 2010 16:22
    Last modified: 05 Sep 2014 05:17

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