Analysis of the pseudoautosomal X-linked geneSYBL1in bipolar affective disorder: Description of a new candidate allele for psychiatric disorders

Abstract

The absence of father-to-son transmission has been observed in a subset of families with bipolar disorder (BPD), suggestive of a susceptibility gene on the sex-linked portion of the X chromosome. This is supported by some genetic linkage studies that have provided evidence for a susceptibility locus near Xq28. We have analyzed one candidate gene on Xq28, SYBL1, which maps to the Xq pseudoautosomal region (PAR). SYBL1 encodes a member of the synaptobrevin family of proteins that is involved in synaptic vesicle docking and membrane transport. Genes in the PAR generally escape X-chromosome inactivation and have an active homolog on the Y chromosome, which would result in an increase in same-sex concordance in paternal transmitted traits. However, SYBL1 is neither expressed on the Y chromosome nor the inactive X chromosome and would therefore be expected to show typical sex-linked transmission. We have screened SYBL1 for mutations that could be tested as candidate alleles in the development of BPD. Following single-strand conformation polymorphism (SSCP) analysis and DNA sequencing, four single nucleotide polymorphisms were detected: a silent mutation at codon 108, two intron mutations without any obvious biological significance, and a G-->C transversion in the polypyrimidine tract at the 3' splice acceptor site preceding exon 8. This polymorphism, which creates a perfect 16/16 stretch of pyrimidines, was analyzed in 110 patients with BPD not selected for sex-linked transmission and 119 control subjects. The results show a statistical trend toward an increase in the frequency of the C allele in males with BPD but not females. Males: chi(2) = 3.46, 1 df, p =.06; Females: chi(2) =.20, 1 df, p =.66.

Sex‐specific association of a common variant of the XG gene with autism spectrum disorders

“…The crossover activity in meiosis in PARs is greater in males than in females [Flaquer et al, 2008[Flaquer et al, , 2009, and the observed same-sex concordance in a paternally transmitted trait is also consistent with PAR inheritance [Crow et al, 1989]. It has been suggested that the PARs may harbor genes for other psychiatric disorders including schizophrenia and bipolar affective disorders [Crow et al, 1994;Saito et al, 2000;Muller et al, 2002;Lencz et al, 2007]; however, they have been largely neglected in systematic genome-wide linkage and association studies [Flaquer et al, 2008[Flaquer et al, , 2009. For example, the Illumina HumanHap550 genotyping platform does not include any SNP markers in the PAR1 region in or near XG/ XGPY2 at chromosome Xp22.33/ Yp11.31 where our novel significant association signal was identified.…”

Sex-specific association between bipolar affective disorder in women and GPR50, an X-linked orphan G protein-coupled receptor

“…MDD however is twice as common in female as compared to male subjects. A number of other groups have reported sex-specific results with X-linked candidate genes in both BPAD 5,13,[32][33][34][35] and MDD. 36 A study of affected sib pairs by Stine et al 37 reported excess allele sharing in affected sister-sister pairs in the Xq26-28 region that was not found in affected brother-brother or brother-sister pairs.…”

The Human Pseudoautosomal Region (PAR): Origin, Function and Future

“…In a subset of families with bipolar affective disorder (BPAD), the absence of father-to-son transmission suggested that a susceptibility gene existed on the sex-linked portion of the X chromosome. Saito et al [25] screened SYBL1 and found a polymorphism (G to C transversion at the intron 7/exon 8 junction) with a statistical trend toward an association with BPAD in males. In addition, Muller et al [26] observed a significantly increased frequency of genotypes homozygous for the C allele in females with BPAD in comparison with controls, thus strengthening the role of the SYBL1 gene as a candidate gene for BPAD.…”