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Cytogenetics Offer Up Another Schizophrenia, Bipolar Candidate Gene

4 January 2010. The membrane lipid transporter gene ABCA13 is identified as a candidate susceptibility factor for schizophrenia and bipolar disorder in a Scottish cohort, according to data from a team led by Ben Pickard, now of the University of Strathclyde in Glasgow, United Kingdom. The study, published in the December 11 issue of the American Journal of Human Genetics, highlights the genetic overlap between major psychiatric disorders by identifying for the first time, the authors write, multiple and combined coding variants in a single gene associated with these disorders.

Pickard and co-first author Helen Knight, now at the University of Cambridge, United Kingdom, led a multi-institution collaboration centered at Edinburgh University that first identified cytogenetic disruption of the ABCA13 gene in a person with schizophrenia. Resequencing of key coding regions in a sample of patients and controls revealed 10 rare variants, which were significantly enriched in schizophrenia and bipolar patients in a much larger sample.

No longer so separate
Historically, schizophrenia and mood disorders have been defined as separate mental disorders. However, recent molecular genetic studies suggest a common origin, and results from a large epidemiological study of nine million Swedes over a 30-year period also support a shared genetic risk for the disorders (see SRF related news story). Lichtenstein and colleagues at the Karolinska Institute in Stockholm found that first-degree relatives of people with schizophrenia are at higher risk for bipolar disorder, and vice versa (see also SRF live discussion).

“Recent genomewide association studies that probe common variation at the whole genome scale in large case-control cohorts have found, and sometimes replicated, significant associations of a number of candidate genes with schizophrenia and bipolar disorder and have found substantial overlap of risk factors between these two illnesses,” Knight and colleagues write, citing a number of studies. At the November 2009 World Congress of Psychiatric Genetics, the Psychiatric GWAS Conortium (PGC) working group discussed efforts to examine common variants that play a role in individual disorders as well as to elucidate the shared genetic risk for disorders such as schizophrenia and bipolar disorder (see SRF related news story).

In addition to common polygenic variation, rare copy number variants (CNVs) may also contribute to overlapping disease risk (see SRF related news story). The study of gross cytogenetic abnormalities (visible to the trained eye under a microscope; see SRF related news story), likewise, can be informative. Interestingly, the ABCA13 findings come from the same group in Scotland, using the same old-fashioned karyotyping as a starting point, that first reported DISC1, the most promising gene candidate to date for schizophrenia and mood disorders.

In the current study, Knight and colleagues identified a schizophrenia patient with a pericentric inversion of chromosome 7 coupled with a translocation between chromosomes 7 and 8. The affected gene belongs to the adenosine triphosphate (ATP)-binding cassette (ABC) superfamily of genes, which code for molecules that transport a variety of substrates across membranes. The authors restricted the resequencing of ABCA13, a very large gene, to selected exons (two transmembrane domains and two cytoplasmic nucleotide binding domains and a hydrophobic membrane-dipping region) in 100 individuals with schizophrenia and 100 controls, and identified 10 non-synonymous rare coding variants.

A new, larger “test” sample of individuals with schizophrenia, bipolar disorder, depression, and controls was then evaluated for variant frequencies. Analysis of affected and unaffected family members of those with mutations in this “test” sample was also undertaken. When taken together, the 10 ABCA13 coding variants were significantly associated with schizophrenia and bipolar disorder. "The population attributable risk of the 10 rare non-synonymous mutations was 2.2 percent for schizophrenia and 4.0 percent for bipolar disorder, suggesting that this gene may have an important role in a subgroup of patients and an influence that crosses traditional diagnostic boundaries," the authors write.

Interestingly, additive effects on risk was suggested by five cases of compound heterozygosity and one case of homozygosity, whereas all controls with risk variants were monoallelic. Five cases possessed more than one rare variant simultaneously, and one case showed that a single rare variant damaged both copies of the gene. In contrast, not a single control possessed more than one copy of a rare variant. This observation leads the authors to suggest that additive and interactive combinations of mutations may contribute to these complex disorders.

Lastly, the authors demonstrated that ABCA13 protein is expressed in mouse and human hippocampus and cortex, brain regions relevant in schizophrenia and bipolar disorder.

In an e-mail to SRF, Pickard speculates, “ABCA13 is involved in the metabolism of an as yet unknown lipid, and this lipid may be important in aspects of neuronal function or development such as neurite outgrowth. There is some precedent to this line of enquiry; a closely related gene, ABCA12, which is mutated in a skin disorder called Harlequin Ichthyosis, results in a failure of the skin cells to secrete a lipid called ceramide, causing a frequently fatal skin malformation in neonates. Something equivalent may be happening in the brains of those with ABCA13 mutations. While this is not in line with established models of psychiatric illness (e.g., dopamine/glutamate hypotheses), the fact that we see the same ABCA13 mutations spanning diagnostic boundaries suggests that it must be regulating a fairly fundamental process.”—J. Meggin Hollister.

Knight HM, Pickard BS, Maclean A, Malloy MP, Soares DC, McRae AF, Condie A, White A, Hawkins W, McGhee K, van Beck M, MacIntyre DJ, Starr JM, Deary IJ, Visscher PM, Porteous DJ, Cannon RE, St Clair D, Muir WJ, Blackwood DH. A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression. Am J Hum Genet. 2009 Dec;85(6):833-46. Abstract

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