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  • 1
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    Shared genetic risk between eating disorder‐ and substance‐use‐related phenotypes: Evidence from genome‐wide association studies
    Wiley ; 2021
    In:  Addiction Biology Vol. 26, No. 1 ( 2021-01)
    Details
    In: Addiction Biology, Wiley, Vol. 26, No. 1 ( 2021-01)
    Abstract: Eating disorders and substance use disorders frequently co‐occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [ r g ], twin‐based = 0.23‐0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome‐wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN] , AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance‐use‐related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism‐based genetic correlations between eating disorder‐ and substance‐use‐related phenotypes. Significant positive genetic associations emerged between AUD and AN ( r g = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN ( r g = 0.23; q 〈 0.0001), and cannabis initiation and AN with binge eating ( r g = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating ( r gs = −0.19 to −0.23; qs 〈 0.04). The genetic correlation between AUD and AN was no longer significant after co‐varying for major depressive disorder loci. The patterns of association between eating disorder‐ and substance‐use‐related phenotypes highlights the potentially complex and substance‐specific relationships among these behaviors.
    Type of Medium: Online Resource
    ISSN: 1355-6215 , 1369-1600
    URL: Issue
    URL: Article
    DOI: 10.1111/adb.v26.1
    DOI: 10.1111/adb.12880
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 1495537-4
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  • 2
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    Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol‐Response Behaviors in Model Organisms
    Wiley ; 2017
    In:  Alcoholism: Clinical and Experimental Research Vol. 41, No. 5 ( 2017-05), p. 911-928
    Details
    In: Alcoholism: Clinical and Experimental Research, Wiley, Vol. 41, No. 5 ( 2017-05), p. 911-928
    Abstract: Alcohol dependence ( AD ) shows evidence for genetic liability, but genes influencing risk remain largely unidentified. Methods We conducted a genomewide association study in 706 related AD cases and 1,748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms (MOs) to assess the role of orthologous genes in ethanol (EtOH)‐response behaviors. We tested 1 primate‐specific gene for expression differences in case/control postmortem brain tissue. Results We detected significant association in COL 6A3 and suggestive association in 2 previously implicated loci, KLF 12 and RYR 3 . None of these signals are significant in replication. A suggestive signal in the long noncoding RNA LOC 339975 is significant in case:control meta‐analysis, but not in a population sample. Knockdown of a COL 6A3 ortholog in Caenorhabditis elegans reduced EtOH sensitivity. Col6a3 expression correlated with handling‐induced convulsions in mice. Loss of function of the KLF 12 ortholog in C. elegans impaired development of acute functional tolerance (AFT). Klf12 expression correlated with locomotor activation following EtOH injection in mice. Loss of function of the RYR 3 ortholog reduced EtOH sensitivity in C. elegans and rapid tolerance in Drosophila . The ryanodine receptor antagonist dantrolene reduced motivation to self‐administer EtOH in rats. Expression of LOC 339975 does not differ between cases and controls but is reduced in carriers of the associated rs11726136 allele in nucleus accumbens (NAc). Conclusions We detect association between AD and COL 6A3 , KLF 12 , RYR 3, and LOC 339975 . Despite nonreplication of COL 6A3 , KLF 12, and RYR 3 signals, orthologs of these genes influence behavioral response to EtOH in MOs, suggesting potential involvement in human EtOH response and AD liability. The associated LOC 339975 allele may influence gene expression in human NAc. Although the functions of long noncoding RNA s are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders.
    Type of Medium: Online Resource
    ISSN: 0145-6008 , 1530-0277
    URL: Issue
    URL: Article
    DOI: 10.1111/acer.2017.41.issue-5
    DOI: 10.1111/acer.13362
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 2046886-6
    detail.hit.zdb_id: 3167872-5
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  • 3
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    Long‐Chain ω ‐3 Levels Are Associated With Increased Alcohol Sensitivity in a Population‐Based Sample of Adolescents
    Wiley ; 2019
    In:  Alcoholism: Clinical and Experimental Research Vol. 43, No. 12 ( 2019-12), p. 2620-2626
    Details
    In: Alcoholism: Clinical and Experimental Research, Wiley, Vol. 43, No. 12 ( 2019-12), p. 2620-2626
    Abstract: The levels of the ω ‐3 long‐chain polyunsaturated fatty acids ( ω ‐3 LC‐PUFAs), including eicosapentaenoic acid ( EPA ) and docosahexaenoic acid (DHA), have been associated with alcohol sensitivity in vertebrate and invertebrate model systems, but prior studies have not examined this association in human samples despite evidence of associations between ω ‐3 LC ‐ PUFA levels and alcohol‐related phenotypes. Both alcohol sensitivity and ω ‐3 LC ‐ PUFA levels are impacted by genetic factors, and these influences may contribute to observed associations between phenotypes. Given the potential for using EPA and DHA supplementation in adjuvant care for alcohol misuse and other outcomes, it is important to clarify how ω ‐3 LC ‐ PUFA levels relate to alcohol sensitivity. Methods Analyses were conducted using data from the Avon Longitudinal Study of Parents and Children. Plasma ω ‐3 LC ‐ PUFA levels were measured at ages 15.5 and 17.5. Participants reported on their initial alcohol sensitivity using the early drinking Self‐Rating of the Effects of Alcohol ( SRE ‐5) scale, for which more drinks needed for effects indicates lower levels of response per drink, at ages 15.5, 16.5, and 17.5. Polygenic liability for alcohol consumption, alcohol problems, EPA levels, and DHA levels was derived using summary statistics from large, publicly available datasets. Linear regressions were used to examine the cross‐sectional and longitudinal associations between ω ‐3 LC ‐ PUFA levels and SRE scores. Results Age 15.5 ω ‐3 LC ‐ PUFA levels were negatively associated with contemporaneous SRE scores and with age 17.5 SRE scores. One modest association ( p  = 0.02) between polygenic liability and SRE scores was observed, between alcohol problems–based polygenic risk scores (PRS) and age 16.5 SRE scores. Tests of moderation by genetic liability were not warranted. Conclusions Plasma ω ‐3 LC ‐ PUFA levels may be related to initial sensitivity to alcohol during adolescence. These data indicate that diet‐related factors have the potential to impact humans’ earliest responses to alcohol exposure.
    Type of Medium: Online Resource
    ISSN: 0145-6008 , 1530-0277
    URL: Issue
    URL: Article
    DOI: 10.1111/acer.v43.12
    DOI: 10.1111/acer.14212
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2046886-6
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  • 4
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    Convergent Evidence From Humans and Drosophila melanogaster Implicates the Transcription Factor MEF2B / Mef2 in Alcohol Sensitivity
    Wiley ; 2019
    In:  Alcoholism: Clinical and Experimental Research Vol. 43, No. 9 ( 2019-09), p. 1872-1886
    Details
    In: Alcoholism: Clinical and Experimental Research, Wiley, Vol. 43, No. 9 ( 2019-09), p. 1872-1886
    Abstract: Self‐Rating of the Effects of Alcohol (SRE) measures level of response to ethanol (EtOH) in humans. Interestingly, there is a positive relationship between the SRE and risk for abusing alcohol, suggesting mechanistic connections between SRE and alcohol abuse. Methods To identify candidate genes with a role in SRE and alcohol‐related behavior more generally, we coupled human genetic analyses with studies in Drosophila melanogaster . We first performed a gene‐based analysis of Genomewide association studies (GWAS) summary statistics for SRE in the Avon Longitudinal Study of Parents and Children sample. Based on prior findings in humans, orthology to fly genes, and the availability of genetic reagents, we selected a subset of these genes for studies on EtOH behavior in Drosophila . Results We found 37 genes with nominal associations in our SRE GWAS. We explored the role of 6 orthologous genes in Drosophila EtOH sedation and rapid tolerance. We found that the transcription factor Mef2 is required for normal EtOH sedation in flies. Pan‐neuronal expression of 2 independent Mef2 RNAi transgenes significantly reduced Mef2 expression and made flies resistant to EtOH sedation. Additionally, flies with multiple independent mutant alleles of Mef2 were also resistant to EtOH sedation, confirming a role for Mef2 in this behavior. Altered expression of Mef2 did not change EtOH rapid tolerance or cause a net change in internal EtOH concentrations. Conclusions Our studies indicate that MEF2B influences SRE in humans and that Mef2 impacts EtOH sedation in Drosophila .
    Type of Medium: Online Resource
    ISSN: 0145-6008 , 1530-0277
    URL: Issue
    URL: Article
    DOI: 10.1111/acer.v43.9
    DOI: 10.1111/acer.14138
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2046886-6
    detail.hit.zdb_id: 3167872-5
    SSG: 15,3
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  • 5
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    The effect of parental drinking on alcohol use in young adults: the mediating role of parental monitoring and peer deviance
    Wiley ; 2018
    In:  Addiction Vol. 113, No. 11 ( 2018-11), p. 2041-2050
    Details
    In: Addiction, Wiley, Vol. 113, No. 11 ( 2018-11), p. 2041-2050
    Abstract: Evidence demonstrating an association between parental alcohol use and offspring alcohol use from robust prospective studies is lacking. We tested the direct and indirect associations between parental and young adult alcohol use via early alcohol initiation, parental monitoring and associating with deviant peers. Design Prospective birth cohort study. Path analysis was used to assess the possible association between parental alcohol use (assessed at 12 years) and alcohol use in young adults (assessed at 18 years) via potential mediators (assessed at 14 and 15.5 years, respectively). Setting South West England. Participants Data were available on 3785 adolescents and their parents from the Avon Longitudinal Study of Parents and Children. Measurements The continuous Alcohol Use Disorders Identification Test (AUDIT) score was used as the primary outcome measure. Maternal alcohol use was defined as light ( 〈  4 units on any day), moderate (≥ 4 units on 1–3 days) and high‐risk (≥ 4 units on ≥ 4 days in 1 week). Partner alcohol use was also defined as light, moderate and high risk. Socio‐economic variables were included as covariates. Findings There was strong evidence of a total effect from maternal alcohol use to young adult alcohol use [moderate: b  = 1.07, 95% confidence interval (CI) = 0.64, 1.49, P   〈  0.001; high risk: b  = 1.71, 95% CI = 1.07, 2.35, P   〈  0.001]. The majority of this association was explained through early alcohol initiation (moderate: b  = 0.14, 95% CI = 0.04, 0.25, P  = 0.01; high risk: b  = 0.24, 95% CI = 0.07, 0.40, P   〈  0.01) and early alcohol initiation/associating with deviant peers (moderate: b  = 0.06, 95% CI = 0.02, 0.10, P  〈  0.01; high risk: b  = 0.10, 95% CI = 0.03, 0.16, P   〈  0.01). There was strong evidence of a remaining direct effect (moderate: b  = 0.81, 95% CI = 0.39, 1.22, P   〈  0.001; high risk: b  = 1.28, 95% CI = 0.65, 1.91, P   〈  0.001). A similar pattern of results was evident for partner alcohol use. Conclusions Young adults whose parents have moderate or high‐risk alcohol consumption are more likely to consume alcohol than those with parents with lower alcohol consumption. This association appears to be partly accounted for by earlier alcohol use initiation and higher prevalence of association with deviant peers.
    Type of Medium: Online Resource
    ISSN: 0965-2140 , 1360-0443
    URL: Issue
    URL: Article
    DOI: 10.1111/add.v113.11
    DOI: 10.1111/add.14280
    Language: English
    Publisher: Wiley
    Publication Date: 2018
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  • 6
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    Parental alcohol use disorder and offspring marital outcomes
    Wiley ; 2019
    In:  Addiction Vol. 114, No. 1 ( 2019-01), p. 81-91
    Details
    In: Addiction, Wiley, Vol. 114, No. 1 ( 2019-01), p. 81-91
    Abstract: We tested whether parental alcohol use disorder (AUD) predicted adult offspring's likelihood of marriage and marriage to an AUD‐affected spouse; whether effects differed as a function of the sex or number of affected parents; and whether they were robust to confounders. Design Sex‐stratified Cox and logistic regression models. Setting Sweden. Participants A total of 1 171 070 individuals (51.40% male) born 1965–75. Measurements Obtained from legal, medical and pharmacy registries. Predictor was parent AUD. Outcomes were marriage and spouse AUD. Adjustments included offspring birth year and AUD; and parental education, marriage, divorce, criminal behavior and drug abuse. Findings Male and female offspring of AUD‐affected parents were more likely to marry at younger ages ( 〈  25), illustrative unadjusted hazard ratio (HR) age 20  = 1.22 (1.17, 1.28) and 1.34 (1.20, 1.39) and were less likely to marry at older ages ( 〉  25), HR age 30  = 0.79 (0.78, 0.81) and 0.82 (0.81, 0.84). Parental AUD was associated with higher odds of having an affected spouse for males and females, odds ratio (OR) = 1.47 (1.38, 1.57) and 1.63 (1.56, 1.70). Effects were more pronounced for those with two versus one AUD‐affected parent and adjustments attenuated effects negligibly. Daughters of affected mothers (versus fathers) were more likely to have AUD‐affected husbands, OR = 1.68 (1.54, 1.84) versus 1.56 (1.48, 1.64), while there was no difference in sons. Conclusions In Sweden, parental alcohol use disorder (AUD) is associated with a higher probability of marriage at younger ages, a lower probability of marriage at older ages and a higher likelihood of marriage to an affected spouse compared with no parental AUD. Most of these effects become stronger when the number of AUD‐affected parents increases from one to two, and most effects hold after controlling for parents’ socio‐economic status, marital history, other externalizing disorders and offspring's own AUD status. Daughters of affected mothers are more likely to have an affected spouse.
    Type of Medium: Online Resource
    ISSN: 0965-2140 , 1360-0443
    URL: Issue
    URL: Article
    DOI: 10.1111/add.v114.1
    DOI: 10.1111/add.14405
    Language: English
    Publisher: Wiley
    Publication Date: 2019
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  • 7
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    Suicidal ideation during adolescence: The roles of aggregate genetic liability for suicide attempts and negative life events in the past year
    Wiley ; 2022
    In:  Journal of Child Psychology and Psychiatry Vol. 63, No. 10 ( 2022-10), p. 1164-1173
    Details
    In: Journal of Child Psychology and Psychiatry, Wiley, Vol. 63, No. 10 ( 2022-10), p. 1164-1173
    Abstract: Suicidal thoughts and behaviors (STB) constitute a central public health concern in adolescence. Previous studies emphasized the difficulty to cope with negative life events during adolescence as a risk factor for STB. Familial and genetic liability has also been documented to explain STB risk. Nevertheless, less is known about aggregate genetic liability and its possible interaction with negative life events. Moreover, information is needed to understand how these factors differently affect STB in boys and girls. Methods We evaluated suicidal ideation at 17 years old and examined the role of aggregate genetic liability, negative life events, and their interaction in a sample of 2,571 adolescents. Aggregate genetic liability was measured using a polygenic score (PGS) for suicide attempts. Negative life events were assessed in the past year and included parental divorce and hospitalizations, death of friends and relatives, bullying, failure‐related events, and involvement with drugs. We conducted univariable and multivariable general linear models stratified by sex and evaluated the interactions between PGS and negative life events in subsequent models. Results Analyses showed that suicidal ideation in boys is associated with failure to achieve something important (estimate = 0.198), bullying (estimate = 0.285), drug use (estimate = 0.325), and parental death (estimate = 0.923). In girls, both aggregate genetic liability (estimate = 0.041) and negative life events (failure at school [estimate = 0.120], failure to achieve something important [estimate = 0.279] , drug use [estimate = 0.395], and bullyi ng [estimate = 0.472]) were associated with suicidal ideation. Interaction analyses suggested that PGS interacted with drug use and failures at school, though this would need additional support. Conclusions These findings represent significant contributions to the fundamental understanding of STB in adolescence, suggesting to monitor the impact of negative life events during adolescence to better prevent suicide risk. Genetic liability is also of importance in girls and might influence the way they respond to environmental threats.
    Type of Medium: Online Resource
    ISSN: 0021-9630 , 1469-7610
    URL: Issue
    URL: Article
    DOI: 10.1111/jcpp.v63.10
    DOI: 10.1111/jcpp.13653
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 1470297-6
    SSG: 5,2
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  • 8
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    Risk of depression in persons with Alzheimer's disease: A national cohort study
    Wiley ; 2024
    In:  Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring Vol. 16, No. 2 ( 2024-04)
    Details
    In: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Wiley, Vol. 16, No. 2 ( 2024-04)
    Abstract: Depression is a risk factor and possible prodromal symptom of Alzheimer's disease (AD), but little is known about subsequent risk of developing depression in persons with AD. METHODS National matched cohort study was conducted of all 129,410 persons diagnosed with AD and 390,088 with all‐cause dementia during 1998–2017 in Sweden, and 3,900,880 age‐ and sex‐matched controls without dementia, who had no prior depression. Cox regression was used to compute hazard ratios (HRs) for major depression through 2018. RESULTS Cumulative incidence of major depression was 13% in persons with AD and 3% in controls. Adjusting for sociodemographic factors and comorbidities, risk of major depression was greater than two‐fold higher in women with AD (HR, 2.21; 95% confidence interval [CI], 2.11–2.32) or men with AD (2.68; 2.52–2.85), compared with controls. Similar results were found for all‐cause dementia. DISCUSSION Persons diagnosed with AD or related dementias need close follow‐up for timely detection and treatment of depression. Highlights In a large cohort, women and men with AD had 〉 2‐fold subsequent risk of depression. Risks were highest in the first year ( 〉 3‐fold) but remained elevated ≥3 years later. Risk of depression was highest in persons aged ≥85 years at AD diagnosis. Persons with AD need close follow‐up for detection and treatment of depression.
    Type of Medium: Online Resource
    ISSN: 2352-8729 , 2352-8729
    URL: Issue
    URL: Article
    DOI: 10.1002/dad2.v16.2
    DOI: 10.1002/dad2.12584
    Language: English
    Publisher: Wiley
    Publication Date: 2024
    detail.hit.zdb_id: 2832898-X
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  • 9
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    Risk of suicidal behavior as a function of alcohol use disorder typologies: A Swedish population‐based study
    Wiley ; 2024
    In:  Addiction Vol. 119, No. 2 ( 2024-02), p. 281-290
    Details
    In: Addiction, Wiley, Vol. 119, No. 2 ( 2024-02), p. 281-290
    Abstract: Alcohol use disorder (AUD) is one of the strongest predictors of suicidal behavior. Here, we measured risk of suicide attempt and death as a function of AUD typologies. Design We used AUD typologies from previous latent class analysis: (i) externalizing subtype (characterized by externalizing symptomatology and early age of onset; individuals in this group have lower education and higher familial/social difficulties); (ii) subtype described by minimal psychopathology; and (iii) internalizing subtype (characterized by internalizing symptomatology and later age of onset; individuals in this group have higher education). We used class membership to predict distal outcomes (attempt and death) and performed regressions to evaluate whether differences in suicidal behavior were explained by the group characteristics (sex, age of onset, number and type of AUD registrations, familial/genetic risk for AUD, externalizing and internalizing behaviors, socio‐economic indicators, marital status and childhood family status). We also evaluated the effect of suicide attempt prior to AUD. Setting and participants Based on longitudinal Swedish registry data, we included 217 074 individuals with AUD born 1950–80. Measurements Suicide attempts were identified using medical registers and deaths using the mortality register. Findings Individuals with the externalizing subtype had higher risks of suicidal behavior than other groups [attempt: externalizing versus minimal psychopathology: odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.35, 1.35; externalizing versus internalizing: OR = 1.47, 95% CI = 1.46, 1.48; death: externalizing versus minimal psychopathology: OR = 1.57, 95% CI = 1.57, 1.58; externalizing versus internalizing: OR = 1.99, 95% CI = 1.93, 2.06]. Individuals with minimal psychopathology had higher risks than those with internalizing symptomatology (attempt: OR = 1.09, 95% CI = 1.08, 1.10, death: OR = 1.26, 95% CI = 1.23, 1.30). These differences were explained by age at registration and were related to the number of registrations, sex, education, family disruption and suicide attempt prior to AUD. Conclusions Among people in Sweden, considering alcohol use disorder (AUD) heterogeneity appears to be a meaningful way to evaluate suicide risk. The highest risk of suicide attempt and death occurs in the externalizing subtype of AUD, followed by the minimal psychopathology subtype, and then the internalizing subtype.
    Type of Medium: Online Resource
    ISSN: 0965-2140 , 1360-0443
    URL: Issue
    URL: Article
    DOI: 10.1111/add.v119.2
    DOI: 10.1111/add.16351
    Language: English
    Publisher: Wiley
    Publication Date: 2024
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  • 10
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    The effect of parental alcohol use on alcohol use disorder in young adulthood: Exploring the mediating roles of adolescent alcohol expectancies and consumption
    Wiley ; 2023
    In:  Journal of Adolescence Vol. 95, No. 4 ( 2023-06), p. 716-728
    Details
    In: Journal of Adolescence, Wiley, Vol. 95, No. 4 ( 2023-06), p. 716-728
    Abstract: Parental alcohol use and problems are risk factors for alcohol use disorder (AUD), and these effects may be mediated by adolescent alcohol expectancies and consumption. In the present study, we tested the direct effects of mothers' and fathers' alcohol consumption on young adult AUD, as well as the indirect effects through adolescent maximum alcohol use, alcohol consumption, and alcohol expectancies. Methods Participants were 5160 individuals (49.1% female) and their biological parents from the Avon Longitudinal Study of Parents and Children, a cohort study of children born in southwestern England during 1991 and 1992. Structural equation modeling (SEM) was used to test associations of mothers' and fathers' alcohol use (assessed when children were 12 years old) with age 24 AUD. Potential mediator variables included the maximum number of alcoholic drinks consumed within a 24‐h period by age 13.5 and alcohol expectancies and alcohol consumption at ages 17 and 20. Results Higher maternal and paternal alcohol use were associated with higher levels of alcohol consumption at age 17. Greater alcohol consumption, in turn, was related to a more severe presentation of AUD. The overall indirect effects of mothers' ( b  = 0.033, 95% confidence interval [CI] = 0.006, 0.059) and fathers' drinking ( b  = 0.041, 95% CI = 0.018, 0.064) on AUD were modest but significant, and were primarily comprised of adolescent alcohol consumption rather than alcohol expectancies. Conclusions Our findings underscore the importance of both mothers' and fathers' drinking for the development of alcohol use and problems across adolescence and young adulthood.
    Type of Medium: Online Resource
    ISSN: 0140-1971 , 1095-9254
    URL: Issue
    URL: Article
    DOI: 10.1002/jad.v95.4
    DOI: 10.1002/jad.12148
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 1469149-8
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