Male-specific association of the 2p25 region with suicide attempt in bipolar disorder.

We previously conducted a genome-wide association study (GWAS) of attempted suicide within bipolar disorder, which implicated common variation in the 2p25 region primarily in males. The top association signal from our GWAS occurred in an intergenic region of 2p25 (p = 5.07 × 10-8) and was supported by two independent studies. In the current study, to better characterize the association of the 2p25 region with attempted suicide, we sequenced the entire 350kb 2p25 region in 476 bipolar suicide attempters and 473 bipolar non-attempters using targeted next-generation sequencing. This fine-mapping project identified 4,681 variants in the 2p25 region. We performed both gene-level and individual-variant tests on our sequencing results and identified 375 variants which were nominally significant (p < 0.05) and three common variants that were significantly associated with attempted suicide in males (corrected p = 0.035, odds ratio (OR) = 2.13). These three variants are in strong linkage disequilibrium with the top variant from our GWAS. Our top five variants are also predicted expression quantitative trait loci (eQTL) for three genes in the 2p25 region based on publicly available brain expression databases. Our sequencing and eQTL data implicate these three genes - SH3YL1, ACP1, and FAM150B - and three additional pathways - androgen receptor, Wnt signaling, and glutamatergic/GABAergic signaling - in the association of the 2p25 region with suicide. The current study provides additional support for an association of the 2p25 region with attempted suicide in males and identifies several candidate genes and pathways that warrant further investigation to understand their role in suicidal behavior.

Targeted sequencing of the LRRTM gene family in suicide attempters with bipolar disorder.

Glutamatergic signaling is the primary excitatory neurotransmission pathway in the brain, and its relationship to neuropsychiatric disorders is of considerable interest. Our previous attempted suicide genome-wide association study, and numerous studies investigating gene expression, genetic variation, and DNA methylation have implicated aberrant glutamatergic signaling in suicide risk. The glutamatergic pathway gene LRRTM4 was an associated gene identified in our attempted suicide genome-wide association study, with association support seen primarily in females. Recent evidence has also shown that glutamatergic signaling is partly regulated by sex-related hormones. The LRRTM gene family encodes neuronal leucine-rich transmembrane proteins that localize to and promote glutamatergic synapse development. In this study, we sequenced the coding and regulatory regions of all four LRRTM gene members plus a large intronic region of LRRTM4 in 476 bipolar disorder suicide attempters and 473 bipolar disorder nonattempters. We identified two male-specific variants, one female- and five male-specific haplotypes significantly associated with attempted suicide in LRRTM4. Furthermore, variants within significant haplotypes may be brain expression quantitative trait loci for LRRTM4 and some of these variants overlap with predicted hormone response elements. Overall, these results provide supporting evidence for a sex-specific association of genetic variation in LRRTM4 with attempted suicide.

Mitotic and Meiotic Functions for the SUMOylation Pathway in the Caenorhabditis elegans Germline.

Meiosis is a highly regulated process, partly due to the need to break and then repair DNA as part of the meiotic program. Post-translational modifications are widely used during meiotic events to regulate steps such as protein complex formation, checkpoint activation, and protein attenuation. In this paper, we investigate how proteins that are obligatory components of the SUMO (small ubiquitin-like modifier) pathway, one such post-translational modification, affect the Caenorhabditis elegans germline. We show that UBC-9, the E2 conjugation enzyme, and the C. elegans homolog of SUMO, SMO-1, localize to germline nuclei throughout prophase I. Mutant analysis of smo-1 and ubc-9 revealed increased recombination intermediates throughout the germline, originating during the mitotic divisions. SUMOylation mutants also showed late meiotic defects including defects in the restructuring of oocyte bivalents and endomitotic oocytes. Increased rates of noninterfering crossovers were observed in ubc-9 heterozygotes, even though interfering crossovers were unaffected. We have also identified a physical interaction between UBC-9 and DNA repair protein MRE-11 ubc-9 and mre-11 null mutants exhibited similar phenotypes at germline mitotic nuclei and were synthetically sick. These phenotypes and genetic interactions were specific to MRE-11 null mutants as opposed to RAD-50 or resection-defective MRE-11 We propose that the SUMOylation pathway acts redundantly with MRE-11, and in this process MRE-11 likely plays a structural role.

Prophase I: Preparing Chromosomes for Segregation in the Developing Oocyte.

Formation of an oocyte involves a specialized cell division termed meiosis. In meiotic prophase I (the initial stage of meiosis), chromosomes undergo elaborate events to ensure the proper segregation of their chromosomes into gametes. These events include processes leading to the formation of a crossover that, along with sister chromatid cohesion, forms the physical link between homologous chromosomes. Crossovers are formed as an outcome of recombination. This process initiates with programmed double-strand breaks that are repaired through the use of homologous chromosomes as a repair template. The accurate repair to form crossovers takes place in the context of the synaptonemal complex, a protein complex that links homologous chromosomes in meiotic prophase I. To allow proper execution of meiotic prophase I events, signaling processes connect different steps in recombination and synapsis. The events occurring in meiotic prophase I are a prerequisite for proper chromosome segregation in the meiotic divisions. When these processes go awry, chromosomes missegregate. These meiotic errors are thought to increase with aging and may contribute to the increase in aneuploidy observed in advanced maternal age female oocytes.