Whole‐gene sequencing investigation ofSAT1in attempted suicide

Abstract

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.

Lineage: Visualizing Multivariate Clinical Data in Genealogy Graphs

“…An example is a shared region in family 601627 with genome-wide significance (p=1.94E-10). A single gene in this region, neurexin 1 ( NRXN1 ), has evidence from the published literature of involvement in psychiatric risk [48] and inconclusive evidence for risk of suicide [54]. The shared region in family 601627 is shared by six cases, shown in Figure S4 in the supplemental material.…”

Assessment of Whole-Exome Sequence Data in Attempted Suicide within a Bipolar Disorder Cohort

“…These studies have identified additional targets that may contribute to the risk of suicidal behavior, but very few implicated sites have been replicated [25,26]. Further, few implicated candidate genes have been deeply assessed for the possibility that rare functional variation within them might contribute to the phenotype [27,28,29]. …”

Interrogation of rare functional variation within bipolar disorder and suicidal behavior cohorts

“…Chapter 4 discusses an effort to completely sequence the candidate gene, SAT1, along with surrounding regulatory features near the gene locus. The complete project and our findings are described in the form of the published manuscript, "Whole-gene sequencing investigation of SAT1 in attempted suicide" (41). We selected the SAT1 gene due to extensive focus this gene has recently received within the literature.…”

“…Further, few implicated candidate genes have been deeply assessed for the possibility that rare functional variation within them might contribute to the phenotype (36,37,41).…”

“…Supplementary figures and tables referenced in this article(39) can be accessed on the publisher's website, www.karger.com/doi/10.1159/000454773, This manuscript(41) describes the investigation of the SB candidate gene, spermidine acetyltransferase 1 (SAT1) via complete sequencing of the gene locus and flanking areas with evidence of regulatory importance. I contributed to our research team, under the direction of Dr. Virginia Willour and Dr. Peter Zandi, by preparing computational methods for identifying subjects and targets to be Casavant and his group, was to generate sequencing targets for SAT1 plus regulatory regions to be sequenced outside of the gene locus.…”