Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths... more Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes acr...
We tested the causality between education and smoking using the natural experiment of discordant ... more We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contrib...
ABSTRACTAimsTo investigate how strongly smoking dependence and smoking dependence motives are ass... more ABSTRACTAimsTo investigate how strongly smoking dependence and smoking dependence motives are associated with depressive symptoms among daily smokers and if these associations are independent of measured confounders and shared familial factors.DesignCross‐sectional individual‐based and within‐pair analyses.SettingFourth wave of the population‐based Finnish Twin Cohort conducted in 2011.Participants918 daily smokers born 1945–1957 (48% men), mean age 59.5 years including 38 twin pairs discordant for depression.MeasurementsDepressive symptoms were assessed using the Center for Epidemiologic Studies Depression scale with a cut off value ≥20 for depression. Smoking dependence was assessed using the Fagerström Test for Cigarette Dependence (FTCD) and smoking dependence motives with three subscales from the multi‐dimensional Brief Wisconsin Inventory of Smoking Dependence Motives (WISDM): primary dependence motives (PDM), affective enhancement (AE), and Taste. Logistic regressions, using ...
We test whether genetic influences that explain individual differences in aggression in early lif... more We test whether genetic influences that explain individual differences in aggression in early life also explain individual differences across the life-course. In two cohorts from The Netherlands (N = 13,471) and Australia (N = 5628), polygenic scores (PGSs) were computed based on a genome-wide meta-analysis of childhood/adolescence aggression. In a novel analytic approach, we ran a mixed effects model for each age (Netherlands: 12–70 years, Australia: 16–73 years), with observations at the focus age weighted as 1, and decaying weights for ages further away. We call this approach a ‘rolling weights’ model. In The Netherlands, the estimated effect of the PGS was relatively similar from age 12 to age 41, and decreased from age 41–70. In Australia, there was a peak in the effect of the PGS around age 40 years. These results are a first indication from a molecular genetics perspective that genetic influences on aggressive behavior that are expressed in childhood continue to play a role l...
DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of geneti... more DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N=15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha=1.2×10−7; Bonferroni correction). In cord blood samples of 2,425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r=0.74, p=0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripherl blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposur...
BackgroundSleep bruxism (SB) and awake bruxism (AB) have been considered different entities, alth... more BackgroundSleep bruxism (SB) and awake bruxism (AB) have been considered different entities, although co‐occurrence between them has been shown. While genetic factors have a marked influence on phenotypic variance in liability to SB, this remains unclear for AB.AimTo examine the degree of co‐occurrence of SB and AB, and whether they have common correlates and also twin similarity of SB and AB bruxism traits by zygosity and sex.MethodsA questionnaire was mailed to all twins born 1945‐1957 in Finland in 2012 (n = 11 766). Age and sex adjusted logistic regression models were used. Twin similarity was assessed using polychoric correlations, and crosstwin‐crosstrait correlations were computed.ResultsThe response rate was 72% (n = 8410). Any SB was reported by 14.8% and ≥ 3 nights weekly by 5.0%. Percentages for any AB were 18.4% and 6.3%, respectively. There was substantial co‐occurrence (29.5%) between SB and AB, and several shared correlates were found. For SB, the polychoric intra‐cla...
Internalising symptoms in childhood and adolescence are as heritable as adult depression and anxi... more Internalising symptoms in childhood and adolescence are as heritable as adult depression and anxiety, yet little is known of their molecular basis. This genome-wide association meta-analysis of internalising symptoms included repeated observations from 64,641 individuals, aged between 3 and 18. The N-weighted meta-analysis of overall internalising symptoms (INToverall) detected no genome-wide significant hits and showed low SNP heritability (1.66%, 95% confidence intervals 0.84-2.48%, Neffective=132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalising symptoms showing the highest heritability (5.63%, 95% confidence intervals 3.08-8.18%). Additive genetic effects on internalising symptoms appeared stable over age, with overlapping estimates of SNP heritability from early-childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the wellbeing spectrum (|rg|> 0.70), as well as with i...
Background Women suffer from psychological distress more often than men. Our aim was to investiga... more Background Women suffer from psychological distress more often than men. Our aim was to investigate the potential contribution of work-family balance to this gender difference. Methods Questionnaire data from the nationally representative 2013 Finnish Regional Health and Well-being Study (target population all adults aged 20 years or over, n = 88 377, response rate 53%), was restricted in the current analysis to those who were working and who had minor children (n = 26 442). Psychological distress was assessed using the Mental Health Index (MHI-5, cut off value < =52). Participants answered six questions on balancing work and family demands (yes/no). We used logistic regression adjusted for age, education and marital status. Results Women reported more distress than men (12.4% and 10.2% respectively, p = 0.000). We found statistically significant interactions between gender and two work-family demands (both p = 0.010): “I sometimes neglect my family when I am wholly absorbed in m...
Background: Nicotine-dependent smokers find it difficult to quit smoking. Additionally, smoking-s... more Background: Nicotine-dependent smokers find it difficult to quit smoking. Additionally, smoking-specific weight concerns may affect smoking cessation although the evidence is controversial. We investigated whether smoking-specific weight concerns predict the probability of cessation and, if so, whether the effect varies according to the level of nicotine dependence. Methods: The study was conducted with a population-based sample of 355 adult daily smokers who participated in the baseline examination in 2007 and in the 2014 follow-up. Baseline nicotine dependence was classified as low or high (Fagerström Test for Nicotine Dependence; 0–3 vs. 4–10 points). Within these groups, we examined whether baseline weight concerns predict smoking status (daily, occasional, ex-smoker) at follow-up by using multinomial logistic regression with adjustment for multiple covariates. Results: Among low-dependent participants at baseline, 28.5% had quit smoking, while among highly dependent participant...
Introduction FTND (Fagerstrӧm test for nicotine dependence) and TTFC (time to smoke first cigaret... more Introduction FTND (Fagerstrӧm test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. Methods Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. Results We found that SORBS2 on 4q35 (p = 4.05 × 10−8), BG182718 on 11q22 (p = 1.02 × 10−8), and AA333164 on 14q21 (p = 4.11 × 10−9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found...
European child & adolescent psychiatry, Jan 17, 2018
Modestly prevalent in the general population (~ 4%), but highly prevalent in prison populations (... more Modestly prevalent in the general population (~ 4%), but highly prevalent in prison populations (> 40%), the diagnosis of antisocial personality disorder (ASPD) involves aggression as one of several possible criteria. Using multiple informants, we aimed to determine if general aggression, as well as direct and indirect subtypes, assessed in early adolescence (ages 12, 14) predict young adulthood ASPD in a population-based sample. Using data from a Finnish population-based longitudinal twin cohort study with psychiatric interviews available at age 22 (N = 1347), we obtained DSM-IV-based ASPD diagnoses. Aggression measures from ages 12 (parental and teacher ratings) and 14 (teacher, self, and co-twin ratings) were used to calculate odds ratios (OR) of ASPD from logistic regression models and the area under the curve (AUC) from receiver operating characteristic curve analysis. Analyses were adjusted for sex, age, and family structure. All informants' aggression ratings were sign...
Understanding molecular processes that link comorbid traits such as addictions and mental disorde... more Understanding molecular processes that link comorbid traits such as addictions and mental disorders can provide novel therapeutic targets. Neuregulin signaling pathway (NSP) has previously been implicated in schizophrenia, a neurodevelopmental disorder with high comorbidity to smoking. Using a Finnish twin family sample, we have previously detected association between nicotine dependence and ERBB4 (a neuregulin receptor), and linkage for smoking initiation at the ERBB4 locus on 2q33. Further, Neuregulin3 has recently been shown to associate with nicotine withdrawal in a behavioral mouse model. In this study, we scrutinized association and linkage between 15 036 common, low frequency and rare genetic variants in 10 NSP genes and phenotypes encompassing smoking and alcohol use. Using the Finnish twin family sample (N=1998 from 740 families), we detected 66 variants (representing 23 LD blocks) significantly associated (false discovery rate P<0.05) with smoking initiation, nicotine d...
Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths... more Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes acr...
We tested the causality between education and smoking using the natural experiment of discordant ... more We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contrib...
ABSTRACTAimsTo investigate how strongly smoking dependence and smoking dependence motives are ass... more ABSTRACTAimsTo investigate how strongly smoking dependence and smoking dependence motives are associated with depressive symptoms among daily smokers and if these associations are independent of measured confounders and shared familial factors.DesignCross‐sectional individual‐based and within‐pair analyses.SettingFourth wave of the population‐based Finnish Twin Cohort conducted in 2011.Participants918 daily smokers born 1945–1957 (48% men), mean age 59.5 years including 38 twin pairs discordant for depression.MeasurementsDepressive symptoms were assessed using the Center for Epidemiologic Studies Depression scale with a cut off value ≥20 for depression. Smoking dependence was assessed using the Fagerström Test for Cigarette Dependence (FTCD) and smoking dependence motives with three subscales from the multi‐dimensional Brief Wisconsin Inventory of Smoking Dependence Motives (WISDM): primary dependence motives (PDM), affective enhancement (AE), and Taste. Logistic regressions, using ...
We test whether genetic influences that explain individual differences in aggression in early lif... more We test whether genetic influences that explain individual differences in aggression in early life also explain individual differences across the life-course. In two cohorts from The Netherlands (N = 13,471) and Australia (N = 5628), polygenic scores (PGSs) were computed based on a genome-wide meta-analysis of childhood/adolescence aggression. In a novel analytic approach, we ran a mixed effects model for each age (Netherlands: 12–70 years, Australia: 16–73 years), with observations at the focus age weighted as 1, and decaying weights for ages further away. We call this approach a ‘rolling weights’ model. In The Netherlands, the estimated effect of the PGS was relatively similar from age 12 to age 41, and decreased from age 41–70. In Australia, there was a peak in the effect of the PGS around age 40 years. These results are a first indication from a molecular genetics perspective that genetic influences on aggressive behavior that are expressed in childhood continue to play a role l...
DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of geneti... more DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N=15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha=1.2×10−7; Bonferroni correction). In cord blood samples of 2,425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r=0.74, p=0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripherl blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposur...
BackgroundSleep bruxism (SB) and awake bruxism (AB) have been considered different entities, alth... more BackgroundSleep bruxism (SB) and awake bruxism (AB) have been considered different entities, although co‐occurrence between them has been shown. While genetic factors have a marked influence on phenotypic variance in liability to SB, this remains unclear for AB.AimTo examine the degree of co‐occurrence of SB and AB, and whether they have common correlates and also twin similarity of SB and AB bruxism traits by zygosity and sex.MethodsA questionnaire was mailed to all twins born 1945‐1957 in Finland in 2012 (n = 11 766). Age and sex adjusted logistic regression models were used. Twin similarity was assessed using polychoric correlations, and crosstwin‐crosstrait correlations were computed.ResultsThe response rate was 72% (n = 8410). Any SB was reported by 14.8% and ≥ 3 nights weekly by 5.0%. Percentages for any AB were 18.4% and 6.3%, respectively. There was substantial co‐occurrence (29.5%) between SB and AB, and several shared correlates were found. For SB, the polychoric intra‐cla...
Internalising symptoms in childhood and adolescence are as heritable as adult depression and anxi... more Internalising symptoms in childhood and adolescence are as heritable as adult depression and anxiety, yet little is known of their molecular basis. This genome-wide association meta-analysis of internalising symptoms included repeated observations from 64,641 individuals, aged between 3 and 18. The N-weighted meta-analysis of overall internalising symptoms (INToverall) detected no genome-wide significant hits and showed low SNP heritability (1.66%, 95% confidence intervals 0.84-2.48%, Neffective=132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalising symptoms showing the highest heritability (5.63%, 95% confidence intervals 3.08-8.18%). Additive genetic effects on internalising symptoms appeared stable over age, with overlapping estimates of SNP heritability from early-childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the wellbeing spectrum (|rg|> 0.70), as well as with i...
Background Women suffer from psychological distress more often than men. Our aim was to investiga... more Background Women suffer from psychological distress more often than men. Our aim was to investigate the potential contribution of work-family balance to this gender difference. Methods Questionnaire data from the nationally representative 2013 Finnish Regional Health and Well-being Study (target population all adults aged 20 years or over, n = 88 377, response rate 53%), was restricted in the current analysis to those who were working and who had minor children (n = 26 442). Psychological distress was assessed using the Mental Health Index (MHI-5, cut off value < =52). Participants answered six questions on balancing work and family demands (yes/no). We used logistic regression adjusted for age, education and marital status. Results Women reported more distress than men (12.4% and 10.2% respectively, p = 0.000). We found statistically significant interactions between gender and two work-family demands (both p = 0.010): “I sometimes neglect my family when I am wholly absorbed in m...
Background: Nicotine-dependent smokers find it difficult to quit smoking. Additionally, smoking-s... more Background: Nicotine-dependent smokers find it difficult to quit smoking. Additionally, smoking-specific weight concerns may affect smoking cessation although the evidence is controversial. We investigated whether smoking-specific weight concerns predict the probability of cessation and, if so, whether the effect varies according to the level of nicotine dependence. Methods: The study was conducted with a population-based sample of 355 adult daily smokers who participated in the baseline examination in 2007 and in the 2014 follow-up. Baseline nicotine dependence was classified as low or high (Fagerström Test for Nicotine Dependence; 0–3 vs. 4–10 points). Within these groups, we examined whether baseline weight concerns predict smoking status (daily, occasional, ex-smoker) at follow-up by using multinomial logistic regression with adjustment for multiple covariates. Results: Among low-dependent participants at baseline, 28.5% had quit smoking, while among highly dependent participant...
Introduction FTND (Fagerstrӧm test for nicotine dependence) and TTFC (time to smoke first cigaret... more Introduction FTND (Fagerstrӧm test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. Methods Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. Results We found that SORBS2 on 4q35 (p = 4.05 × 10−8), BG182718 on 11q22 (p = 1.02 × 10−8), and AA333164 on 14q21 (p = 4.11 × 10−9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found...
European child & adolescent psychiatry, Jan 17, 2018
Modestly prevalent in the general population (~ 4%), but highly prevalent in prison populations (... more Modestly prevalent in the general population (~ 4%), but highly prevalent in prison populations (> 40%), the diagnosis of antisocial personality disorder (ASPD) involves aggression as one of several possible criteria. Using multiple informants, we aimed to determine if general aggression, as well as direct and indirect subtypes, assessed in early adolescence (ages 12, 14) predict young adulthood ASPD in a population-based sample. Using data from a Finnish population-based longitudinal twin cohort study with psychiatric interviews available at age 22 (N = 1347), we obtained DSM-IV-based ASPD diagnoses. Aggression measures from ages 12 (parental and teacher ratings) and 14 (teacher, self, and co-twin ratings) were used to calculate odds ratios (OR) of ASPD from logistic regression models and the area under the curve (AUC) from receiver operating characteristic curve analysis. Analyses were adjusted for sex, age, and family structure. All informants' aggression ratings were sign...
Understanding molecular processes that link comorbid traits such as addictions and mental disorde... more Understanding molecular processes that link comorbid traits such as addictions and mental disorders can provide novel therapeutic targets. Neuregulin signaling pathway (NSP) has previously been implicated in schizophrenia, a neurodevelopmental disorder with high comorbidity to smoking. Using a Finnish twin family sample, we have previously detected association between nicotine dependence and ERBB4 (a neuregulin receptor), and linkage for smoking initiation at the ERBB4 locus on 2q33. Further, Neuregulin3 has recently been shown to associate with nicotine withdrawal in a behavioral mouse model. In this study, we scrutinized association and linkage between 15 036 common, low frequency and rare genetic variants in 10 NSP genes and phenotypes encompassing smoking and alcohol use. Using the Finnish twin family sample (N=1998 from 740 families), we detected 66 variants (representing 23 LD blocks) significantly associated (false discovery rate P<0.05) with smoking initiation, nicotine d...
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