Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age.

The genetic contribution to the variation in human lifespan is ∼ 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥ 90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

Whole-gene sequencing investigation of SAT1 in attempted suicide.

Suicidal behavior imposes a tremendous cost, with current US estimates reporting approximately 1.3 million suicide attempts and more than 40,000 suicide deaths each year. Several recent research efforts have identified an association between suicidal behavior and the expression level of the spermidine/spermine N1-acetyltransferase 1 (SAT1) gene. To date, several SAT1 genetic variants have been inconsistently associated with altered gene expression and/or directly with suicidal behavior. To clarify the role SAT1 genetic variation plays in suicidal behavior risk, we present a whole-gene sequencing effort of SAT1 in 476 bipolar disorder subjects with a history of suicide attempt and 473 subjects with bipolar disorder but no suicide attempts. Agilent SureSelect target enrichment was used to sequence all exons, introns, promoter regions, and putative regulatory regions identified from the ENCODE project within 10 kb of SAT1. Individual variant, haplotype, and collapsing variant tests were performed. Our results identified no variant or assessed region of SAT1 that showed a significant association with attempted suicide, nor did any assessment show evidence for replication of previously reported associations. Overall, no evidence for SAT1 sequence variation contributing to the risk for attempted suicide could be identified. It is possible that past associations of SAT1 expression with suicidal behavior arise from variation not captured in this study, or that causal variants in the region are too rare to be detected within our sample. Larger sample sizes and broader sequencing efforts will likely be required to identify the source of SAT1 expression level associations with suicidal behavior. © 2016 Wiley Periodicals, Inc.

A targeted sequencing study of glutamatergic candidate genes in suicide attempters with bipolar disorder.

Suicidal behavior has been shown to have a heritable component that is partly driven by psychiatric disorders [Brent and Mann, 2005]. However, there is also an independent factor contributing to the heritability of suicidal behavior. We previously conducted a genome-wide association study (GWAS) of bipolar suicide attempters and bipolar non-attempters to assess this independent factor [Willour et al., 2012]. This GWAS implicated glutamatergic neurotransmission in attempted suicide. In the current study, we have conducted a targeted next-generation sequencing study of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, neurexin, and neuroligin gene families in 476 bipolar suicide attempters and 473 bipolar non-attempters. The goal of this study was to gather sequence information from coding and regulatory regions of these glutamatergic genes to identify variants associated with attempted suicide. We identified 186 coding variants and 4,298 regulatory variants predicted to be functional in these genes. No individual variants were overrepresented in cases or controls to a degree that was statistically significant after correction for multiple testing. Additionally, none of the gene-level results were statistically significant following correction. While this study provides no direct support for a role of the examined glutamatergic candidate genes, further sequencing in expanded gene sets and datasets will be required to ultimately determine whether genetic variation in glutamatergic signaling influences suicidal behavior. © 2016 Wiley Periodicals, Inc.

Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder.

FKBP5 is a critical component of the Hypothalamic-Pituitary-Adrenal (HPA) axis, a system which regulates our response to stress. It forms part of a complex of chaperones, which inhibits binding of cortisol and glucocorticoid receptor translocation to the nucleus. Variations in both the HPA axis and FKBP5 have been associated with suicidal behavior. We developed a systematic, targeted sequencing approach to investigate coding and regulatory regions in or near FKBP5 in 476 bipolar disorder suicide attempters and 473 bipolar disorder non-attempters. Following stringent quality control checks, we performed single-variant, gene-level and haplotype tests on the resulting 481 variants. Secondary analyses investigated whether sex-specific variations in FKBP5 increased the risk of attempted suicide. One variant, rs141713011, showed an excess of minor alleles in suicide attempters that was statistically significant following correction for multiple testing (Odds Ratio = 6.65, P-value = 7.5 x 10-4, Permuted P-value = 0.038). However, this result could not be replicated in an independent cohort (Odds Ratio = 0.90, P-value = 0.78). Three female-specific and four male-specific variants of nominal significance were also identified (P-value < 0.05). The gene-level and haplotype association tests did not produce any significant results. This comprehensive study of common and rare variants in FKBP5 focused on both regulatory and coding regions in relation to attempted suicide. One rare variant remained significant following correction for multiple testing but could not be replicated. Further investigation is required in larger sample sets to fully elucidate the association of this variant with suicidal behavior.

Investigating the role of early childhood abuse and HPA axis genes in suicide attempters with bipolar disorder.

OBJECTIVE: Genes and the environment both play a major role in the risk for attempted suicide, and environments harboring stressors, such as early childhood abuse, have been linked to suicidal behavior. Such environments also disrupt the hypothalamic-pituitary-adrenal (HPA) axis pathway, which has been hypothesized to play a role in suicidal behavior. We investigated whether the risk for attempted suicide was attributable in part to the interaction between childhood physical and/or sexual abuse and genetic variation in 19 genes (±5 kb) integral to the HPA axis pathway. MATERIALS AND METHODS: Using the Genetic Association Information Network Bipolar Disorder and Translational Genomics Research Institute cohorts, we implemented PLINK's logistic regression-based 'interaction' approach to search for evidence of an interaction between 235 genotyped HPA axis single-nucleotide polymorphisms and early childhood abuse. Our study included 631 bipolar disorder suicide attempters and 657 bipolar disorder nonattempters with information on abuse. RESULTS: After correction for multiple testing, no significant interaction between the 235 HPA axis single-nucleotide polymorphisms and early childhood abuse was found. In our study, the strongest interaction was found with rs2664008 in the corticotropin-releasing hormone receptor 1 (CRHR1) gene, with a nominal interaction P-value of 1.22×10 and an interaction odds ratio of 0.47. CONCLUSION: Our findings suggest that further work and larger sample sizes are required to elucidate the link between early childhood abuse and the HPA axis in suicidal behavior.