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Studies have suggested that Research Diagnostic Criteria for Schizoaffective Disorder Bipolar type (RDC-SABP) might identify a more genetically homogenous subgroup of bipolar disorder. Aiming to identify loci associated with RDC-SABP, we have performed a replication study using independent RDC-SABP cases (n = 144) and controls (n = 6,559), focusing on the 10 loci that reached a p-value <10 -5 for RDC-SABP in the Wellcome Trust Case Control Consortium (WTCCC) bipolar disorder sample. Combining the WTCCC and replication datasets by meta-analysis (combined RDC-SABP, n = 423, controls, n = 9,494), we observed genome-wide significant association at one SNP, rs2352974, located within the intron of the gene TRAIP on chromosome 3p21.31 (p-value, 4.37 × 10 -8 ). This locus did not reach genome-wide significance in bipolar disorder or schizophrenia large Psychiatric Genomic Consortium datasets, suggesting that it may represent a relatively specific genetic risk for the bipolar subtype of schizoaffective disorder., (© 2017 Wiley Periodicals, Inc.)

The GWAS-based association of CACNA1C with bipolar disorder (BPD) is one of the strongest genetic findings to date. CACNA1C belongs to the family of CACN genes encoding voltage-dependent calcium channels (VDCCs). VDCCs are involved in brain circuits and cognitive processes implicated in BPD and schizophrenia (SZ). Recently, it was shown that rare copy number variations (CNVs) are found at an increased frequency in SZ and to a lesser extent also in BPD, suggesting the involvement of CNVs in the causation of these diseases. We hypothesize that CNVs in CACN genes can influence the susceptibility to BPD, SZ, and/or schizoaffective disorder (SZA). A search for CNVs in eight CACN genes in a patient-control sample of European decent was performed. A total of 709 BP patients, 645 SZ patients, 189 SZA patients, and 1,470 control individuals were screened using the Multiplex Amplicon Quantification (MAQ) method. We found a rare, partial deletion of 35.7 kb in CACNA2D4 in two unrelated late onset bipolar I patients and in one control individual. All three deletions shared the same breakpoints removing exons 17-26 of CACNA2D4, comprising part of the CACHE domain. Based on the data we cannot claim causality to BPD of the identified CACNA2D4 deletion but nevertheless this deletion can be important in unraveling the underlying processes leading to psychiatric diseases in general and BPD in particular., (Copyright © 2012 Wiley Periodicals, Inc.)

We have previously reported evidence that variation at GABA(A) receptor genes is associated with susceptibility to bipolar disorder with schizophrenia-like psychotic features (Research Diagnostic Criteria (RDC) schizoaffective disorder, bipolar type) with gene-wide significance at GABRB1, GABRA4, GABRB3, GABRA5, and GABRR3. Here we provide suggestive evidence implicating a sixth member of the gene family, GABRR1 (gene-wide P = 0.0058; experiment-wide corrected significance P = 0.052).

The chromosomal region 12q24 has been previously implicated by linkage studies of both bipolar disorder and unipolar mood disorder and we have reported two pedigrees segregating both bipolar disorder and Darier's disease that show linkage across this region. The gene P2RX7 is located in this chromosomal region and has been recently reported as a susceptibility gene for bipolar disorder and unipolar depression. The non-synonymous SNP rs2230912 (resulting in amino-acid polymorphism Q460R) showed the strongest association and has been postulated to be pathogenically relevant. We have investigated this gene in a large UK case-control sample (bipolar I disorder N = 687, unipolar recurrent major depression N = 1,036, controls N = 1,204). Neither rs2230912 nor any of 8 other SNPs genotyped across P2RX7 was found to be associated with mood disorder in general, nor specifically with bipolar or unipolar disorder. Further, sequencing of our two chromosome 12-linked bipolar-Darier families showed no evidence of rare variants at P2RX7 that could explain the linkage. Our data do not provide support for rs2230912 or the other polymorphisms studied within the P2RX7 locus, being involved in susceptibility to mood disorders., (2009 Wiley-Liss, Inc.)