Genome-Wide Association Study Meta-Analysis of Suicide Attempt in 43,871 Cases Identifies Twelve Genome-Wide Significant Loci

Docherty, Anna; Mullins, Niamh; Ashley–Koch, Allison; Shabalin, Andrey A.; Murnyák, Balázs; Kang, Jooeun; Qin, Xuejun; DiBlasi, Emily; Coon, Hilary; Kimbrel, Nate; Beckham, Jean C.; Ruderfer, Douglas M.

doi:10.1016/j.euroneuro.2022.07.060

Cited by 13 publications

(17 citation statements)

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“…Most previous candidate gene analyses and GWAS for completed suicides could not overcome the statistical limitation of sample sizes because it is extremely difficult to obtain tissue samples from suicide completers 25,26 . Second, it would be difficult to use only a single candidate gene approach to identify susceptibility genes for a complex phenotype such as suicide, and a combined analysis of multiple genes or loci, including the risk loci of suicidal attempters identified by Docherty et al., 21 would be required. Third, our study only included Japanese participants.…”

Section: Discussionmentioning

confidence: 99%

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Association study of a single nucleotide polymorphism in the hypoxia response element of the macrophage migration inhibitory factor gene promoter with suicide completers in the Japanese population

Shirai,

Okazaki,

Tanifuji

et al. 2024

Neuropsychopharm Rep

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BackgroundMore than 800 000 people die by suicide annually. The heritability of suicide is 30%–50%. We focused on the hypoxia response element (HRE), which promotes the expression of macrophage migration inhibitory factor (MIF) via the hypoxia‐inducible factor (HIF) pathway, important in neurogenesis and neuroprotection. We examined a genetic polymorphism of rs17004038, a single‐nucleotide polymorphism (SNP), in suicide completers and controls.MethodsThe study population included 1336 suicide completers and 814 unrelated healthy controls. All participants were Japanese. We obtained peripheral blood, extracted DNA, and genotyped the patients for SNP rs17004038 (C > A).ResultsNo significant differences were observed between the two groups in either the allele or genotype analyses. Subgroup analyses by sex, age (<40 or ≥40), and suicide method (violent or nonviolent suicide) were performed with similar results.ConclusionNo association was observed between SNP rs17004038 and suicide completion. Although it is challenging to collect a large number of samples from suicide completers, further MIF‐related genetic studies, including those of rs17004038, are necessary with larger sample sizes.

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Section: Discussionmentioning

confidence: 99%

“…Our previous study of MIF in patients with schizophrenia has failed to obtain information from each patient on suicidal risk, including suicidal ideation. 17 Docherty et al 21 conducted meta-analysis integrating GWAS for patients with suicidal behaviors, identifying 12 risk loci. However, most studies did not target suicide deaths.…”

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confidence: 99%

Association study of a single nucleotide polymorphism in the hypoxia response element of the macrophage migration inhibitory factor gene promoter with suicide completers in the Japanese population

Shirai,

Okazaki,

Tanifuji

et al. 2024

Neuropsychopharm Rep

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“…The largest GWAS meta-analysis to date (with ~ 959K individuals) reported 12 loci for suicide attempt. Risk loci were mostly intergenic and implicated genes DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2 (30). Intriguingly, one of the genes, ROBO2, reported by the ISGC GWAS to be associated with SB (31) is on a rare run-of-homozygosity (ROH) segment that was previously reported to be linked to severe AUD in an American Indian population (38).…”

Section: Introductionmentioning

confidence: 99%

“…In recent years, numerous large genome-wide association studies (GWAS) have been reported for suicidal behaviors (28, [30][31][32][33][34]. These studies were carried out in populations dominated by individuals of European descent.…”

Section: Introductionmentioning

confidence: 99%

Genetic Factors Associated with Suicidal Behaviors and Alcohol Use Disorders in an American Indian Population

Gilder¹,

Bernert

Karriker‐Jaffe³

et al. 2023

Preprint

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American Indians (AI) demonstrate the highest rates of both suicidal behaviors (SB) and alcohol use disorders (AUD) among all ethnic groups in the US. Rates of suicide and AUD vary substantially between tribal groups and across different geographical regions, underscoring a need to delineate more specific risk and resilience factors. Using data from over 740 AI living within eight contiguous reservations, we assessed genetic risk factors for SB by investigating: (1) possible genetic overlap with AUD, and (2) impacts of rare and low frequency genomic variants. Suicidal behaviors included lifetime history of suicidal thoughts and acts, including verified suicide deaths, scored using a ranking variable for the SB phenotype (range 0–4). We identified five loci significantly associated with SB and AUD, two of which are intergenic and three intronic on genes AACSP1, ANK1, and FBXO11. Nonsynonymous rare mutations in four genes including SERPINF1 (PEDF), ZNF30, CD34, and SLC5A9, and non-intronic rare mutations in genes OPRD1, HSD17B3 and one lincRNA were significantly associated with SB. One identified pathway related to hypoxia-inducible factor (HIF) regulation, whose 83 nonsynonymous rare variants on 10 genes were significantly linked to SB as well. Four additional genes, and two pathways related to vasopressin-regulated water metabolism and cellular hexose transport, also were strongly associated with SB. This study represents the first investigation of genetic factors for SB in an American Indian population that has high risk for suicide. Our study suggests that bivariate association analysis between comorbid disorders can increase statistical power; and rare variant analysis in a high-risk population enabled by whole-genome sequencing has the potential to identify novel genetic factors. Although such findings may be population specific, rare functional mutations relating to PEDF and HIF regulation align with past reports and suggest a biological mechanism for suicide risk and a potential therapeutic target for intervention.

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“…In this sense, the GWAS on attention‐deficit/hyperactivity disorder (ADHD) (Demontis et al., 2023) might help to add previously unknown components to the physiology of attention and cognition. Also, GWAS on major depression (Levey et al., 2021) and suicide behaviours (Docherty et al., 2022; Mullins et al., 2022) can contribute to our understanding of the biology underlying subjective well‐being, while the GWAS on migraines (Hautakangas et al., 2022) has the potential to unravel mechanisms involved in pain. However, there is enormous scope to study intermediate variables that have essential physiological functions (e.g.…”

Section: Introductionmentioning

confidence: 99%

Genome‐wide association studies: utility and limitations for research in physiology

Pereira Ciochetti,

Lugli‐Moraes,

Santos da Silva

et al. 2023

The Journal of Physiology

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Physiological systems are subject to interindividual variation encoded by genetics. Genome‐wide association studies (GWAS) operate by surveying thousands of genetic variants from a substantial number of individuals and assessing their association to a trait of interest, be it a physiological variable, a molecular phenotype (e.g. gene expression), or even a disease or condition. Through a myriad of methods, GWAS downstream analyses then explore the functional consequences of each variant and attempt to ascertain a causal relationship to the phenotype of interest, as well as to delve into its links to other traits. This type of investigation allows mechanistic insights into physiological functions, pathological disturbances and shared biological processes between traits (i.e. pleiotropy). An exciting example is the discovery of a new thyroid hormone transporter (SLC17A4) and hormone metabolising enzyme (AADAT) from a GWAS on free thyroxine levels. Therefore, GWAS have substantially contributed with insights into physiology and have been shown to be useful in unveiling the genetic control underlying complex traits and pathological conditions; they will continue to do so with global collaborations and advances in genotyping technology. Finally, the increasing number of trans‐ancestry GWAS and initiatives to include ancestry diversity in genomics will boost the power for discoveries, making them also applicable to non‐European populations.

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Genome-Wide Association Study Meta-Analysis of Suicide Attempt in 43,871 Cases Identifies Twelve Genome-Wide Significant Loci

Cited by 13 publications

References 0 publications

Association study of a single nucleotide polymorphism in the hypoxia response element of the macrophage migration inhibitory factor gene promoter with suicide completers in the Japanese population

Association study of a single nucleotide polymorphism in the hypoxia response element of the macrophage migration inhibitory factor gene promoter with suicide completers in the Japanese population

Genetic Factors Associated with Suicidal Behaviors and Alcohol Use Disorders in an American Indian Population

Genome‐wide association studies: utility and limitations for research in physiology

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