| 1. |
- Docherty, Anna R, et al.
(author)
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
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In: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
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Journal article (peer-reviewed)abstract
- Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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| 2. |
- Edwards, Alexis C., et al.
(author)
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Alcohol Use Disorder and Risk of Suicide in a Swedish Population-Based Cohort
- 2020
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In: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 177:7, s. 627-634
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The authors examined the association between alcohol use disorder (AUD) and risk of suicide, before and after accounting for psychiatric comorbidity, and assessed the extent to which the observed association is due to a potentially causal mechanism or genetic and familial environmental confounding factors that increase risk for both. METHODS: Longitudinal population-wide Swedish medical, criminal, and pharmacy registries were used to evaluate the risk of death by suicide as a function of AUD history. Analyses employed prospective cohort and co-relative designs, including data on 2,229,880 native Swedes born between 1950 and 1970 and observed from age 15 until 2012. RESULTS: The lifetime rate of suicide during the observation period was 3.54% for women and 3.94% for men with AUD, compared with 0.29% and 0.76% of women and men, respectively, without AUD. In adjusted analyses, AUD remained robustly associated with suicide: hazard ratios across observation periods ranged from 2.61 to 128.0 among women and from 2.44 to 28.0 among men. Co-relative analyses indicated that familial confounding accounted for some, but not all, of the observed association. A substantial and potentially causal relationship remained after accounting for a history of other psychiatric diagnoses. CONCLUSIONS: AUD is a potent risk factor for suicide, with a substantial association persisting after accounting for confounding factors. These findings underscore the impact of AUD on suicide risk, even in the context of other mental illness, and implicate the time frame shortly after a medical or criminal AUD registration as critical for efforts to reduce alcohol-related suicide.
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| 3. |
- Edwards, Alexis C., et al.
(author)
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Protective Effects of Pregnancy on Risk of Alcohol Use Disorder
- 2019
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In: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 176:2, s. 138-145
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Journal article (peer-reviewed)abstract
- OBJECTIVE:: The authors sought to clarify the etiology of the association between pregnancy and reduced risk of alcohol use disorder. METHODS:: The authors used data from longitudinal population-wide Swedish medical, pharmacy, and criminal registries to evaluate whether rates of alcohol use disorder are lower during pregnancy. They compared pregnant women born between 1975 and 1992 (N=322,029) with matched population controls, with female relatives discordant for pregnancy, and with pre- and postpregnancy periods within individuals. They further compared rates of alcohol use disorder between pregnant women and their partners. RESULTS:: Pregnancy was inversely associated with alcohol use disorder across all analyses (odds ratios, 0.17-0.32). In co-relative analyses, the strength of the association increased among more closely related individuals. Within individuals, rates of alcohol use disorder were substantially decreased during pregnancy relative to the prepregnancy period (odds ratios, 0.25-0.26), and they remained reduced during postpartum periods (odds ratios, 0.23-0.31). Results were similar for second pregnancies (odds ratio, 0.23). The partners of pregnant women also exhibited reductions in alcohol use disorder (odds ratio, 0.45). Among women who became pregnant at earlier ages and those with a history of criminal behavior, the negative association between pregnancy and alcohol use disorder was especially pronounced, but no moderation was observed for a personal or maternal parental history of alcohol use disorder. CONCLUSIONS:: The findings suggest that pregnancy plays a critical, and likely causal, motivational role in reducing alcohol use disorder risk among women and, to a lesser extent, their partners. These results extend our understanding of the relationship between pregnancy and alcohol use, demonstrating that even a severe condition such as alcohol use disorder is subject to the protective effects of pregnancy.
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| 4. |
- Kendler, Kenneth S., et al.
(author)
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An Extended Swedish Adoption Study of Anxiety Disorder and Its Cross-Generational Familial Relationship With Major Depression
- 2022
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In: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 179:9, s. 640-649
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To clarify, using an extended adoption design, the sources of parent-offspring transmission for anxiety disorder (AD) and its major subforms and their familial cross-generational relationship with major depression (MD). METHODS: Offspring (born 1960-1992) and their parents, from six family types (intact, not-lived-with biological father or mother, lived-with step-father or step-mother, and adoptive), were ascertained from Swedish national samples. Diagnoses were obtained from national medical registers. We assessed three sources of parent-child resemblance: genes plus rearing, genes only, and rearing only. To test comorbidity effects, single diagnoses were assigned in comorbid cases based on frequency and recency. RESULTS: For AD to AD parent-child transmission, best-estimate tetrachoric correlations for the three types of parent-offspring relationships genes plus rearing, genes only, and rearing only-equaled +0.16 (95% CI=0.16, 0.16), +0.12 (95% CI=0.10, 0.13), and +0.06 (95% CI=0.04, 0.07), respectively, with broadly similar results for MD to MD transmission. Cross-disorder cross-generation correlations were modestly lower, with genetic and rearing correlations for AD and MD estimated at +0.83 (95% CI=0.76, 0.90) and +0.83 (95% CI=0.69, 0.96), respectively. Analyses for panic disorder and generalized anxiety disorder (GAD) produced comparable findings, with the genetic correlation with MD modestly higher for generalized anxiety disorder than panic disorder. Applying a diagnostic hierarchy to comorbid cases resulted in a decline in cross-disorder cross-generation transmission with the estimated genetic correlation equaling +0.46 (95% CI=0.30, 0.62). CONCLUSIONS AND RELEVANCE: For AD and its major subforms, cross-generational transmission includes both genetic and rearing effects. In traditional analyses, AD and MD demonstrate highly correlated genetic and rearing effects. The genetic correlation weakened when applying a diagnostic hierarchy.
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| 5. |
- Kendler, Kenneth S., et al.
(author)
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Divorce and the onset of alcohol use disorder : A Swedish population-based longitudinal cohort and co-relative study
- 2017
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In: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 174:5, s. 451-458
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Journal article (peer-reviewed)abstract
- Objective: The purpose of this study was to clarify the magnitude and nature of the relationship between divorce and risk for alcohol use disorder (AUD). Method: In a population-based Swedish sample of married individuals (N=942,366), the authors examined the association between divorce or widowhood and risk for first registration for AUD. AUD was assessed usingmedical, criminal, and pharmacy registries. Results: Divorcewas strongly associatedwith risk for first AUD onset in bothmen (hazard ratio=5.98, 95% CI=5.65-6.33) and women (hazard ratio=7.29, 95% CI=6.72-7.91). The hazard ratio was estimated for AUD onset given divorce among discordant monozygotic twins to equal 3.45 and 3.62 in men andwomen, respectively. Divorcewas also associatedwith an AUD recurrence in those with AUD registrations before marriage. Furthermore,widowhood increased risk for AUD inmen (hazard ratio=3.85, 95% CI=2.81-5.28) and women (hazard ratio=4.10, 95% CI=2.98-5.64). Among divorced individuals, remarriage was associated with a large decline in AUD in both sexes (men: hazard ratio=0.56, 95% CI=0.52-0.64; women: hazard ratio=0.61, 95% CI=0.55-0.69). Divorce produced a greater increase in first AUDonset in thosewith a family history of AUD or with prior externalizing behaviors. Conclusions: Spousal loss through divorce or bereavement is associated with a large enduring increased AUD risk. This association likely reflects both causal and noncausal processes. That the AUD status of the spouse alters this association highlights the importance of spouse characteristics for the behavioral health consequences of spousal loss. The pronounced elevation in AUD risk following divorce or widowhood, and the protective effect of remarriage against subsequent AUD, speaks to the profound impact of marriage on problematic alcohol use.
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| 6. |
- Kendler, Kenneth S., et al.
(author)
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Effect of marriage on risk for onset of alcohol use disorder : A longitudinal and co-relative analysis in a swedish national sample
- 2016
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In: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 173:9, s. 911-918
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Journal article (peer-reviewed)abstract
- Objective: The authors sought to clarify the relationship between marriage and risk for alcohol use disorder. Method: The association between marital status and risk for first registration for alcohol use disorder in medical, criminal, and pharmacy registries was assessed in a population-based Swedish cohort (N=3,220,628) using longitudinal timedependent survival and co-relative designs. Results: First marriage was associated with a substantial decline in risk for onset of alcohol use disorder in men (hazard ratio=0.41, 95% CI=0.40-0.42) and women (hazard ratio=0.27, 95% CI=0.26-0.28). This association was slightly stronger when the spouse had no lifetime alcohol use disorder, while marriage to a spouse with lifetime alcohol use disorder increased risk for subsequent alcohol use disorder registration in both men (hazard ratio=1.29, 95% CI=1.16-1.43) and women (hazard ratio=1.18, 95% CI=1.06-1.30). In both sexes, the protective effect of marriage was significantly stronger in those with than those without a family history of alcohol use disorder. In both men and women, the associations between marriage and risk for alcohol use disorder in cousins, half siblings, full siblings, and monozygotic twins discordant for marital status were as strong as that seen in the general population. Conclusions: First marriage to a spouse with no lifetime alcohol use disorder is associated with a large reduction in risk for alcohol use disorder. This association cannot be explained by standard covariates or, as indicated by corelative analyses, familial genetic or shared environmental confounders. These results are consistent with the hypothesis that the psychological and social aspects of marriage, and in particular health-monitoring spousal interactions, strongly protect against the development of alcohol use disorder. The protective effects of marriage on risk for alcohol use disorder are increased in those at high familial risk for alcoholism.
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| 7. |
- Kendler, Kenneth S., et al.
(author)
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Genetic and Family and Community Environmental Effects on Drug Abuse in Adolescence: A Swedish National Twin and Sibling Study
- 2014
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In: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 171:2, s. 209-217
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Journal article (peer-reviewed)abstract
- Objective: Using Swedish nationwide registry data, the authors investigated genetic and environmental risk factors in the etiology of drug abuse by twin sibling modeling. The authors followed up with epidemiological analyses to identify shared environmental influences on drug abuse. Method: Drug abuse was defined using public medical, legal, or pharmacy records. Twin and sibling pairs were obtained from the national twin and genealogical registers. Information about sibling pair residence within the same household, small residential area, or municipality was obtained from Statistics Sweden. The authors predicted concordance for drug abuse by years of co-residence until the older sibling turned 21 and risk for future drug abuse in adolescents living with parental figures as a function of family-level socioeconomic status and neighborhood social deprivation. Results: The best twin sibling fit model predicted substantial heritability for drug abuse in males (55%) and females (73%), with environmental factors shared by siblings operating only in males and accounting for 23% of the variance in liability. For each year of living in the same household, the probability of sibling concordance for drug abuse increased 2%-5%. When not residing in the same household, concordance was predicted from residence in the same small residential area or municipality. Risk for drug abuse was predicted both by family socioeconomic status and neighborhood social deprivation. Controlling for family socioeconomic status, each year of living in a high social deprivation neighborhood increased the risk for drug abuse by 2%. Conclusions: Using objective registry data, the authors found that drug abuse is highly heritable. A substantial proportion of the shared environmental effect on drug abuse comes from community-wide rather than household-level influences. Genetic effects demonstrated in twin studies have led to molecular analyses to elucidate biological pathways. In a parallel manner, environmental effects can be followed up by epidemiological studies to clarify social mechanisms.
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| 8. |
- Kendler, Kenneth S., et al.
(author)
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Pattern of Risks for Psychiatric and Substance Use Disorders in the Offspring of Parents With Alcohol Use Disorder
- 2024
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In: The American journal of psychiatry. - 1535-7228. ; 181:4, s. 322-329
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The authors sought to clarify the components of the familial liability to alcohol use disorder (AUD) by examining parent-offspring transmission in a large Swedish population sample. METHODS: To this end, 1,244,516 offspring in intact families with a mean age at follow-up of 37.7 years (SD=6.8) were examined. Hazard ratios for offspring of parents with AUD were calculated using Cox models for risk of five disorders assessed from Swedish medical and criminal registries: AUD, drug use disorders, attention deficit hyperactivity disorder, major depression, and anxiety disorders. RESULTS: The hazard ratio for the offspring was highest for AUD (hazard ratio=2.36), followed by drug use disorder (hazard ratio=2.04), attention deficit hyperactivity disorder (hazard ratio=1.82), major depression (hazard ratio=1.43), and anxiety disorder (hazard ratio=1.43). The risks for AUD were statistically indistinguishable between the children having mothers with AUD compared with those having fathers with AUD and between sons and daughters of a parent with AUD. All risks for offspring having two parents with AUD were higher than those having one parent with AUD, but the increase with two parents with AUD was greatest for AUD, followed by drug use disorder and attention deficit hyperactivity disorder. Age at AUD onset of the parents predicted risk among the offspring more strongly for AUD and drug use disorder, followed by attention deficit hyperactivity disorder, and then major depression and anxiety disorders. Number of recurrences of the parents with AUD predicted risks for all disorders equally. The risk pattern of disorders for the offspring of not-lived-with fathers with AUD was similar to that in the main analysis of intact families. No evidence was found for sex-specific transmission of AUD or a familial female protective effect. CONCLUSIONS: Familial and likely genetic liability to AUD has three components: a nonspecific risk of common internalizing and externalizing disorders, a moderately specific risk of externalizing disorders, and a highly specific risk of AUD.
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| 9. |
- Kendler, Kenneth S., et al.
(author)
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The protective effect of pregnancy on risk for drug abuse : A population, Co-relative, Co-spouse, and within-individual analysis
- 2017
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In: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 174:10, s. 954-962
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Journal article (peer-reviewed)abstract
- Objective: The authors sought to determine whether pregnancy is an intrinsic motivator for cessation of drug abuse. Method: The authors conducted prospective cohort, corelative, co-spouse, and within-person analyses of registration for drug abuse during pregnancy among Swedish women born between 1980 and 1990 who gave birth between ages 20 and 35 (N=149,512). Drug abuse was assessed from medical, criminal, and pharmacy registries. Results: In the population, rates of drug abuse were lower during pregnancy (unadjusted odds ratio=0.67,95%CI=0.60, 0.74). Compared with population results, the negative association between pregnancy and drug abuse was moderately stronger in cousins (odds ratio=0.49,95%CI=0.39, 0.62) and substantially stronger in siblings (odds ratio=0.35, 95% CI=0.24, 0.51) discordant for pregnancy. The estimated odds ratio for drug abuse in pregnancy-discordant monozygotic twins was even stronger, at 0.17 (95% CI=0.10, 0.31). Within individuals, the odds ratio for drug abuse while pregnant compared with an equivalent prepregnancy interval was similar to that seen in pregnancy-discordant monozygotic twins, at 0.22 (95% CI=0.19, 0.26). Compared with cohabiting fathers, mothers had a greater reduction in risk for drug abuse during pregnancy (odds ratio=0.40, 95% CI=0.34, 0.47). Pregnancy was more protective in women with low parental education and without a cohabiting, actively drug-abusing father. Compared with prepregnancy baseline, withinindividual analyses indicate that risk for drug abuse is also substantially reduced in the postpartum period, for example, the odds ratio for postpartum days 0-242 was 0.13 (95% CI=0.11, 0.16). Conclusions: Risk for drug abuse in women is substantially reduced during pregnancy. Multiple analyses suggest that this association is largely causal, suggesting that pregnancy is indeed a strong intrinsic motivator for drug abuse cessation. Similar strong protective effects may be present in the immediate postpartum period. Our results have implications for our etiologic models of drug abuse and especially for contingency management programs seeking to reduce drug abuse risk.
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| 10. |
- Kendler, Kenneth S., et al.
(author)
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The Rearing Environment and Risk for Major Depression : A Swedish National High-Risk Home-Reared and Adopted-Away Co-Sibling Control Study
- 2020
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In: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 177:5, s. 447-453
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Journal article (peer-reviewed)abstract
- Objective: The authors sought to clarify the role of rearing environment in the etiology of major depression. Methods: Defining high risk as having at least one biological parent with major depression, the authors identified a Swedish National Sample of 666 high-risk full sibships and 2,596 high-risk half sibships containing at least one homereared and one adopted-away sibling. Major depression was assessed from national medical registries. Results: Controlling for sex, parental age at birth, and, for half siblings, history of major depression in the nonshared parent, the risk for major depression in the matched adopted compared with home-reared full and half siblings was reduced by 23% (95% CI=7-36) and by 19% (95% CI=10-38), respectively. This protective rearing effect was not influenced by the relative educational status of the biological and adoptive parents. However, in both full and half sibships, the protective effect of adoption disappeared when an adoptive parent or stepsibling had major depression or the adoptive home was disrupted by parental death or divorce. Conclusions: In matched full and half sibships at high risk for major depression, compared with individuals raised in their home environment, those reared in adoptive homes (homes selected in Sweden for their high-quality rearing environment) had a significantly reduced risk for major depression. This protective effect disappeared if an adoptive parent had major depression or if the adoptive home experienced parental death or divorce during childhood/adolescence. The rearing environment has a meaningful impact on risk for major depression, and this effect is likely mediated both by parental depression and the continuity or disruption of the home environment.
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