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

Knight, Helen M., Pickard, Benjamin S., Maclean, Alan, Malloy, Mary P., Soares, Dinesh C., McRae, Allan F., Condie, Alison, White, Angela, Hawkins, William, McGhee, Kevin, van Beck, Margaret, MacIntyre, Donald J., Starr, John M., Deary, Ian J., Visscher, Peter M., Porteous, David J., Cannon, Ronald E., St Clair, David, Muir, Walter J. and Blackwood, Douglas H. R. (2009) A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression. American Journal of Human Genetics, 85 6: 833-846. doi:10.1016/j.ajhg.2009.11.003


Author Knight, Helen M.
Pickard, Benjamin S.
Maclean, Alan
Malloy, Mary P.
Soares, Dinesh C.
McRae, Allan F.
Condie, Alison
White, Angela
Hawkins, William
McGhee, Kevin
van Beck, Margaret
MacIntyre, Donald J.
Starr, John M.
Deary, Ian J.
Visscher, Peter M.
Porteous, David J.
Cannon, Ronald E.
St Clair, David
Muir, Walter J.
Blackwood, Douglas H. R.
Title A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
1537-6605
Publication date 2009
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2009.11.003
Volume 85
Issue 6
Start page 833
End page 846
Total pages 14
Place of publication Cambridge, MA, United States
Publisher Cell Press
Language eng
Abstract Schizophrenia and bipolar disorder are leading causes of morbidity across all populations, with heritability estimates of ∼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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
 
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Created: Tue, 02 Apr 2013, 13:56:00 EST by Allan Mcrae on behalf of UQ Diamantina Institute