A Cytogenetic Abnormality and Rare Coding Variants Identify ABCA13 as a Candidate Gene in Schizophrenia, Bipolar Disorder, and Depression

Abstract

Schizophrenia and bipolar disorder are leading causes of morbidity across all populations, with heritability estimates of approximately 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.

Investigation of rare non-synonymous variants at ABCA13 in schizophrenia and bipolar disorder

“…Stratification (in one or both studies) is unlikely as most of the samples used in each study have also been included in single-nucleotide polymorphismbased genome-wide association studies, in which there was no evidence that this made an appreciable impact. 1,2,3 Regarding genotyping artefacts, we have no specific reason to propose that this explains the discrepant results. Addressing our own study, the genotyping clusters for all markers were excellent, automated and manual calls by two independent experienced researchers blind to the results of the other were 100% congruent, as were duplicate genotypes for each of the markers in 5% of the sample.…”

“…1 The gene was targeted following the observation of a complex chromosomal rearrangement, inv(7) (p12.3;q21.11), t(7;8)(p12.3;p23) in an individual with severe chronic schizophrenia. 1 Only one breakpoint disrupted a gene, that at 7p12.3 to which maps ABCA13. This led the authors to postulate the involvement of rare non-synonymous variants at ABCA13 in major psychiatric disorders.…”

Transcriptional regulation of neurodevelopmental and metabolic pathways by NPAS3

“…Immunofluorescence of frozen brain sections was carried out as previously described (20). Antibodies against Npas3, Gfap, Dcx and Nestin were all obtained from Santa Cruz Biotechnology.…”

The Effects of Neurological Disorder-Related Codon Variations of ABCA13 on the Function of the ABC Protein

“…3) In the present study, we found for the first time that ABCA13 is expressed in Purkinje cells, the only projection neurons in the cerebellum (Fig. 5).…”

“…ABCA13 is the largest member of the ABC protein family and has a long N-terminal, including more than 3,500 amino acids. It is expressed as mRNA in the human trachea, testis, bone marrow, brain, and other tissues, [1][2][3] but its physiological function remains unknown.…”