Risks associated with parental separation have received limited attention in research on children of parents with substance use disorders. We examined early substance involvement as a function of parental separation during childhood and parental alcohol and cannabis dependence.
Data were drawn from 1,318 adolescent offspring of monozygotic (MZ) or dizygotic (DZ) Australian twin parents. Cox proportional hazards regression analyses were conducted predicting age at first use of alcohol, first alcohol intoxication, first use and first regular use of cigarettes, and first use of cannabis, from parental separation and both parent and cotwin substance dependence. Parent and cotwin alcohol and cannabis dependence were initially modeled separately, with post-hoc tests for equality of effects.
With few exceptions, risks associated with parental alcohol versus cannabis dependence could be equated, with results largely suggestive of genetic transmission of risk from parental substance (alcohol or cannabis) dependence broadly defined. Controlling for parental substance dependence, parental separation was a strong predictor for all substance use variables, especially through age 13.
Together, findings underscore the importance of parental separation as a risk-factor for early substance involvement over and above both genetic and environmental influences specific to parental alcohol and cannabis dependence.
adolescent substance use; parental separation; parental substance dependence; children of twins
Genes encoding the opioid receptors (OPRM1, OPRD1, and
OPRK1) are obvious candidates for involvement in risk for
heroin dependence. Prior association studies commonly had samples of modest
size, included limited single nucleotide polymorphism (SNP) coverage of these
genes, and yielded inconsistent results. Participants for the current
investigation included 1459 heroin dependent cases ascertained from maintenance
clinics in New South Wales, Australia, 1495 unrelated individuals selected from
an Australian sample of twins and siblings as not meeting DSM-IV criteria for
lifetime alcohol or illicit drug dependence (non-dependent controls), and 531
controls ascertained from economically-disadvantaged neighborhoods in proximity
to the maintenance clinics. A total of 136 OPRM1, OPRD1, and
OPRK1 SNPs were genotyped in this sample. After controlling
for admixture with principal components analysis, our comparison of cases to
non-dependent controls found 4 OPRD1 SNPs in fairly high
linkage disequilibrium for which adjusted p values remained significant (e.g.,
rs2236857; OR 1.25; p=2.95 × 10−4) replicating a
previously reported association. A post-hoc analysis revealed that the two-SNP
(rs2236857 and rs581111) GA haplotype in OPRD1 is associated
with greater risk (OR 1.68; p=1.41 × 10−5). No
OPRM1 or OPRK1 SNPs reached more than
nominal significance. Comparisons of cases to neighborhood controls reached only
nominal significance. Our results replicate a prior report providing strong
evidence implicating OPRD1 SNPs and, in particular, the two SNP
(rs2236857 and rs581111) GA haplotype in liability for heroin dependence.
Support was not found for similar association involving either
OPRM1 or OPRK1 SNPs.
association study; heroin dependence; OPRD1; OPRK1; OPRM1
The objective of this study was to examine if earlier onset of drinking and smoking behaviors predicted early sexual intercourse onset using a genetically informed, discordant twin analysis.
3424 adult same-sex twins from the Australian Twin Registry completed a structured interview which included retrospective reports on onsets of smoking, drinking, intoxication and sexual intercourse and conduct disorder symptoms. A two-level frailty model estimated within-twin-pair and between-twin-pair comparisons. Onsets of smoking, drinking, drunkenness and conduct disorder symptoms were estimated as sexual intercourse onset predictors.
After controlling for conduct disorder, smoking and drinking onset did not predict sexual intercourse onset for either within-twin-pair or between-twin-pair comparisons. Drunkenness onset had a significant effect on sexual intercourse onset, such that twins who first experienced alcohol intoxication at a younger age than their co-twins were also more likely to have sex earlier than their co-twins.
Relationships between substance use and sexual intercourse onsets may be due mostly to shared underlying factors; there was only a small relation between intoxication onset and sexual intercourse onset, and no direct relation between smoking and drinking onset and sexual intercourse onset.
Twin study; sexual intercourse onset; substance use onset; problem behavior theory
Compared to the association between cigarette smoking and psychiatric disorders, relatively little is known about the relationship between smokeless tobacco use and psychiatric disorders. To identify the psychiatric correlates of smokeless tobacco use, the analysis used a national representative sample from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) wave 1. Smokeless tobacco use was classified as exclusive snuff use, exclusive chewing tobacco, and dual use of both snuff and chewing tobacco at some time in the smokeless tobacco user's life. Lifetime psychiatric disorders were obtained via structured diagnostic interviews. The results show that the prevalence of lifetime exclusive snuff use, exclusive chewing tobacco, and dual use of both snuff and chewing tobacco was 2.16%, 2.52%, and 2.79%, respectively. After controlling for sociodemographic variables and cigarette smoking, the odds of exclusive chewing tobacco in persons with panic disorder and specific phobia were 1.53 and 1.41 times the odds in persons without those disorders, respectively. The odds of exclusive snuff use, exclusive chewing tobacco, and dual use of both products for individuals with alcohol use disorder were 1.97, 2.01, and 2.99 times the odds for those without alcohol use disorder, respectively. Respondents with cannabis use disorder were 1.44 times more likely to use snuff exclusively than those without cannabis use disorder. Respondents with inhalant/solvent use disorder were associated with 3.33 times the odds of exclusive chewing tobacco. In conclusion, this study highlights the specific links of anxiety disorder, alcohol, cannabis, and inhalant/solvent use disorders with different types of smokeless tobacco use.
Genetic risk for alcohol dependence has been shown to overlap with genetic factors contributing to variation in dimensions of personality. Though drinking motives have been posited as important mediators of the alcohol-personality relation, the extent to which the genetic covariance between alcohol use disorder (AUD) symptoms (i.e. abuse and dependence criteria) and personality is explained by genetic factors contributing to variation in drinking motives remains unclear.
Using data from 2,904 young adult female twins, the phenotypic and genetic associations among personality dimensions (constraint [measured by the Multidimensional Personality Questionnaire; Tellegen, 1982], conscientiousness, neuroticism, and agreeableness [measured by the NEO-PI; Costa & McCrae, 1985]), internal drinking motives (enhancement and coping motives [measured by the Drinking Motive Questionnaire; Cooper, 1994]), and AUD symptoms were tested.
Significant genetic associations were found between all personality measures and AUD symptoms. Coping motives showed significant genetic overlap with AUD symptoms and most personality measures, whereas enhancement motives were not significantly heritable. Adjusting for coping motives, genetic correlations between AUD symptoms and traits of neuroticism and agreeableness were no longer statistically significant.
Findings suggest that genetic variation in drinking to cope might account for a considerable proportion of the genetic covariance between specific personality dimensions and AUD symptoms.
behavior genetics; personality; drinking motives; alcohol use disorders
Given moderately strong genetic contributions to variation in alcoholism and heaviness of drinking (50–60% heritability), with high correlation of genetic influences, we have conducted a quantitative trait genomewide association study for phenotypes related to alcohol use and dependence.
Diagnostic interview and blood/buccal samples were obtained from sibships ascertained through the Australian Twin Registry. Genomewide SNP genotyping was performed with 8754 individuals [2062 alcohol dependent cases] selected for informativeness for alcohol use disorder and associated quantitative traits. Family-based association tests were performed for alcohol dependence, dependence factor score and heaviness of drinking factor score, with confirmatory case-population control comparisons using an unassessed population control series of 3393 Australians with genomewide SNP data.
No findings reached genomewide significance (p=8.4×10−8 for this study), with lowest p-value for primary phenotypes of 1.2×10−7. Convergent findings for quantitative consumption and diagnostic and quantitative dependence measures suggest possible roles for a transmembrane protein gene (TMEM108) and for ANKS1A. The major finding, however, was small effect sizes estimated for individual SNPs, suggesting that hundreds of genetic variants make modest contributions (1/4% of variance or less) to alcohol dependence risk.
We conclude that (i) meta-analyses of consumption data may contribute usefully to gene-discovery; (ii) translation of human alcoholism GWAS results to drug discovery or clinically useful prediction of risk will be challenging; (iii) through accumulation across studies, GWAS data may become valuable for improved genetic risk differentiation in research in biological psychiatry (e.g. prospective high-risk or resilience studies).
Alcoholism; genome-wide association; quantitative-trait; non-replication
The manifestation of alcohol dependence at different developmental stages may be associated with different genetic and environmental factors. Taking a developmental approach, the current study characterized interaction between the dopamine receptor 4 variable number tandem repeat (DRD4 VNTR) polymorphism and developmentally specific environmental factors (childhood adversity, college/Greek involvement, and delayed adult role transition) on alcohol dependence during emerging and young adulthood. Prospective data were obtained from a cohort of 234 Caucasian individuals (56% female) followed up at ages 18 through 34. A longitudinal hierarchical factor model was estimated to model a trait-like persistent alcohol dependence factor throughout emerging and young adulthood and two residual state-like alcohol dependence factors limited to emerging adulthood and young adulthood, respectively. To account for those alcohol dependence factors, three two-way interaction effects between the DRD4 VNTR polymorphism and the three developmentally specific environment factors were modeled. Carriers of the DRD4 long allele showed greater susceptibility to environmental effects; they showed more persistent alcohol dependence symptoms as childhood adversity increased and more alcohol dependence symptoms limited to emerging adulthood as college/Greek involvement increased. Alcohol dependence among non-carriers of the long allele, however, did not differ as a function of those environments. Although replication is necessary, these findings highlight the importance of repeated phenotypic assessments across development and modeling both distal and proximal environments and their interaction with genetic susceptibility at specific developmental stages.
DRD4 VNTR; alcohol; gene-environment interaction; development
Smoking is a major risk factor for several somatic diseases, and is also
emerging as a causal factor for neuropsychiatric disorders. Genome-wide
association (GWA) and candidate gene studies for smoking behavior and nicotine
dependence (ND) have disclosed too few predisposing variants to account for the
high estimated heritability. Prior large-scale GWA studies have had very limited
phenotypic definitions of relevance to smoking-related behavior, which has
likely impeded the discovery of genetic effects. We performed genome-wide
association analyses on 1114 adult twins ascertained for ever smoking from the
population-based Finnish Twin Cohort study. The availability of 17
smoking-related phenotypes allowed us to comprehensively portray the dimensions
of smoking behavior, clustered into the domains of smoking initiation, amount
smoked, and ND. Our results highlight a locus on 16p12.3, with several SNPs in
the vicinity of CLEC19A showing association
(P<1×10−6) with smoking
quantity. Interestingly, CLEC19A is located close to a
previously reported attention deficit hyperactivity disorder (ADHD) linkage
locus and an evident link between ADHD and smoking has been established.
Intriguing preliminary association
(P<1×10−5) was detected
between DSM-IV ND diagnosis and several SNPs in ERBB4, coding
for a Neuregulin receptor, on 2q33. The association between
ERBB4 and DSM-IV ND diagnosis was replicated in an
independent Australian sample. Interestingly, in the paper by Turner et al.,
significant increase in ErbB4 and Neuregulin 3 (Nrg3) expression was revealed
following chronic nicotine exposure and withdrawal in mice. Turner et al. also
detected an association between NRG3 SNPs and smoking cessation
success in a clinical trial. ERBB4 has previously been
associated with schizophrenia; further, it is located within an established
schizophrenia linkage locus and within a linkage locus for a smoker phenotype
identified in this sample. As a conclusion, we disclose novel tentative evidence
for the involvement of ERBB4 in ND, suggesting the involvement
of the Neuregulin/ErbB signalling pathway in addictions and providing a
plausible link between the high co-morbidity of schizophrenia and ND.
genome-wide association analysis; nicotine dependence; smoking behavior; smoking quantity; schizophrenia; ADHD
Differences in age at initiation of alcohol use and rates of problem drinking between African Americans (AA) and European Americans (EA) are well documented, but the association between early and problem use – and distinctions by ethnic group in this association - have yet to be examined in a genetically-informative framework.
Data were derived from a longitudinal study of female twins in Missouri. The sample was composed of 3,532 twins (13.6% AA, 86.4% EA) who participated in the fourth wave of data collection and reported consumption of at least one alcoholic drink over the lifetime. Mean age at Wave 4 was 21.7 (range=18–29) years. Twin modeling was conducted to estimate the relative contributions of additive genetic (A), shared environmental (C), and unique environmental (E) factors to variation in age at first drink and problem alcohol use and the cross-phenotype overlap in these influences.
Early initiation of alcohol use predicted problem use in EA but not AA women. Separate AA and EA twin models produced substantially different estimates (but not statistically different models) of the relative contributions of A and C to problem alcohol use but similar genetic correlations between the phenotypes. Whereas 33% of the variance in the EA model of problem use was attributed to C, no evidence for C was found in the AA model. Heritability estimates for problem alcohol use were 41% in the AA model, 21% in the EA model. Evidence for A and C were found in both AA and EA models of age at first drink, but the A estimate was higher in the EA than AA model (44% vs. 26%).
Findings are suggestive of distinctions between AA vs. EA women in the relative contribution of genetic and environmental influences on the development of problem drinking.
alcohol; African Americans; women; twins
Genetic variation affecting absorption, distribution or excretion of essential trace elements may lead to health effects related to sub-clinical deficiency. We have tested for allelic effects of single-nucleotide polymorphisms (SNPs) on blood copper, selenium and zinc in a genome-wide association study using two adult cohorts from Australia and the UK. Participants were recruited in Australia from twins and their families and in the UK from pregnant women. We measured erythrocyte Cu, Se and Zn (Australian samples) or whole blood Se (UK samples) using inductively coupled plasma mass spectrometry. Genotyping was performed with Illumina chips and >2.5 m SNPs were imputed from HapMap data. Genome-wide significant associations were found for each element. For Cu, there were two loci on chromosome 1 (most significant SNPs rs1175550, P = 5.03 × 10−10, and rs2769264, P = 2.63 × 10−20); for Se, a locus on chromosome 5 was significant in both cohorts (combined P = 9.40 × 10−28 at rs921943); and for Zn three loci on chromosomes 8, 15 and X showed significant results (rs1532423, P = 6.40 × 10−12; rs2120019, P = 1.55 × 10−18; and rs4826508, P = 1.40 × 10−12, respectively). The Se locus covers three genes involved in metabolism of sulphur-containing amino acids and potentially of the analogous Se compounds; the chromosome 8 locus for Zn contains multiple genes for the Zn-containing enzyme carbonic anhydrase. Where potentially relevant genes were identified, they relate to metabolism of the element (Se) or to the presence at high concentration of a metal-containing protein (Cu).
While the genetic contribution to the development of anorexia nervosa (AN) has long been recognized, there has been little progress relative to other psychiatric disorders in identifying specific susceptibility genes. Here we have carried out a GWAS on an unselected community sample of female twins surveyed for eating disorders.
We conducted genome wide association analyses in 2564 female twins for four different phenotypes derived from self-report data relating to lifetime presence of 15 types of disordered eating: anorexia nervosa spectrum, bulimia nervosa spectrum, purging via substances, and a binary measure of no disordered eating behaviors versus 3 or more. To complement the variant level results we also conducted gene-based association tests using VEGAS.
While no variants reached genome-wide significance at the level of p<10−8, six regions were suggestive (p<5×10−7). The current results implicate the following genes: CLEC5A; LOC136242, TSHZ1 and SYTL5 for the anorexia nervosa spectrum phenotype, NT5C1B for the bulimia nervosa spectrum phenotype, and ATP8A2 for the disordered eating behaviors phenotype.
As with other medical and psychiatric phenotypes, much larger samples and meta-analyses will ultimately be needed to identify genes and pathways contributing to predisposition to eating disorders.
While initiation of cannabis use is around 40% heritable, not much is known about the underlying genetic etiology. Here, we meta-analysed two genome-wide association studies of initiation of cannabis use with (>10,000 individuals). None of the genetic variants reached genome-wide significance. We also performed a gene-based association test, which also revealed no significant effects of individual genes. Finally, we estimated that only approximately 6.0% of the variation in cannabis initiation is due to common genetic variants. Future genetic studies using larger sample sizes and different methodologies (including sequencing) might provide more insight in the complex genetic etiology of cannabis use.
genetics; cannabis; heritability; association
Personality traits are complex phenotypes related to psychosomatic health. Individually, various gene finding methods have not achieved much success in finding genetic variants associated with personality traits. We performed a meta-analysis of four genome-wide linkage scans (N=6149 subjects) of five basic personality traits assessed with the NEO Five-Factor Inventory. We compared the significant regions from the meta-analysis of linkage scans with the results of a meta-analysis of genome-wide association studies (GWAS) (N∼17 000). We found significant evidence of linkage of neuroticism to chromosome 3p14 (rs1490265, LOD=4.67) and to chromosome 19q13 (rs628604, LOD=3.55); of extraversion to 14q32 (ATGG002, LOD=3.3); and of agreeableness to 3p25 (rs709160, LOD=3.67) and to two adjacent regions on chromosome 15, including 15q13 (rs970408, LOD=4.07) and 15q14 (rs1055356, LOD=3.52) in the individual scans. In the meta-analysis, we found strong evidence of linkage of extraversion to 4q34, 9q34, 10q24 and 11q22, openness to 2p25, 3q26, 9p21, 11q24, 15q26 and 19q13 and agreeableness to 4q34 and 19p13. Significant evidence of association in the GWAS was detected between openness and rs677035 at 11q24 (P-value=2.6 × 10−06, KCNJ1). The findings of our linkage meta-analysis and those of the GWAS suggest that 11q24 is a susceptible locus for openness, with KCNJ1 as the possible candidate gene.
personality; KCNJ1; NEO; linkage; GSMA
Several aspects of sleep behaviour such as timing, duration and quality have been demonstrated to be heritable. To identify common variants that influence sleep traits in the population, we conducted a genome-wide association study of 6 sleep phenotypes assessed by questionnaire in a sample of 2,323 individuals from the Australian Twin Registry. Genotyping was performed on the Illumina 317K, 370K and 610K arrays and the common Single Nucleotide Polymorphisms between platforms were used to impute non-genotyped SNPs. We tested for association with more than 2,000,000 common polymorphisms across the genome. While no SNPs reached the genome-wide significance threshold, we identified a number of associations in plausible candidate genes. Most notably, a group of SNPs in the 3rd intron of the CACNA1C gene ranked as most significant in the analysis of sleep latency (p = 1.3 × 10−6). We attempted to replicate this association in an independent sample from the Chronogen Consortium (n = 2,034), but found no evidence of association (p = 0.73). We have identified several other associations that await replication in an independent sample. Our study had good power to detect common single nucleotide polymorphisms that explain more than 2% of the phenotypic variance in self-report sleep phenotypes at a genome-wide significant level. No such variants were detected.
insomnia; genetics; mood; sleep; circadian
DSM-IV specifies a hierarchal diagnostic structure such that an ODD diagnosis is applied only if criteria are not met for CD. Genetic studies of ODD and CD support a combination of shared genetic and environmental influences, but largely ignore the imposed diagnostic structure.
We examined whether ODD and CD share an underlying etiology while accounting for DSM-IV diagnostic specifications. Data from 1446 female twin pairs, aged 11–19, were fitted to two-stage models adhering to the DSM-IV diagnostic hierarchy.
Models suggested that DSM-IV ODD-CD covariation is attributed largely to shared genetic influences.
This is the first study, to our knowledge, to examine genetic and environmental overlap among these disorders while maintaining DSM-IV hierarchical structure. Findings reflect primarily shared genetic influences and specific (i.e., uncorrelated) shared/familial environmental effects on these DSM-IV defined behaviors. These results have implications for how best to define CD and ODD for future genetically-informed analyses.
adolescence; conduct disorder; genetics; oppositional defiant disorder; twins
The effects of sibship size and structure on delinquency are well established. Specifically, having a large family and many brothers has been shown to predict offending. However, despite strong links between delinquency and alcohol use, the contribution of sibship factors to drinking behaviors remains largely unexplored. The current study investigated the impact of sibship size and composition on younger brothers’ and sisters’ ages of drinking and intoxication onset.
We employed a sample of 4,281 same-sex twins from the Australian Twin Register to examine whether: (1) large sibship size facilitates earlier age at first drink (AFD) and age at first intoxication (AFI) in males and females; (2) having many older brothers predicts earlier ages of AFD and AFI in males; and (3) having many older brothers results in later AFD and AFI in females. We tested whether effects were moderated by parental divorce and alcohol misuse and mediated by familial religion.
Sibling effects were minimal before accounting for family context. However, when parental divorce and excessive parental drinking were included as moderators, sibling effects were significantly amplified among individuals from homes of divorce, and effects were strongest when siblings were close in age.
Strong close in age older (CIAO) sibling effects indicate that proximal sibling attitudes and behaviors about alcohol likely interact with structural factors to influence younger siblings' drinking. Sibship factors were much more influential in one population (individuals from homes of divorce) than another (respondents with parental history of excessive drinking), suggesting that sibling effects vary depending on the type of co-occurring familial risk. Prevention efforts performed at the family level, and introduced before first use of alcohol, are likely to delay drinking initiation and help prevent future alcohol problems.
age at first drink; siblings; sibship composition; close in age; twins
Mega- or meta-analytic studies (e.g. genome-wide association studies) are increasingly used in behavior genetics. An issue in such studies is that phenotypes are often measured by different instruments across study cohorts, requiring harmonization of measures so that more powerful fixed effect meta-analyses can be employed. Within the Genetics of Personality Consortium, we demonstrate for two clinically relevant personality traits, Neuroticism and Extraversion, how Item-Response Theory (IRT) can be applied to map item data from different inventories to the same underlying constructs. Personality item data were analyzed in >160,000 individuals from 23 cohorts across Europe, USA and Australia in which Neuroticism and Extraversion were assessed by nine different personality inventories. Results showed that harmonization was very successful for most personality inventories and moderately successful for some. Neuroticism and Extraversion inventories were largely measurement invariant across cohorts, in particular when comparing cohorts from countries where the same language is spoken. The IRT-based scores for Neuroticism and Extraversion were heritable (48 and 49 %, respectively, based on a meta-analysis of six twin cohorts, total N = 29,496 and 29,501 twin pairs, respectively) with a significant part of the heritability due to non-additive genetic factors. For Extraversion, these genetic factors qualitatively differ across sexes. We showed that our IRT method can lead to a large increase in sample size and therefore statistical power. The IRT approach may be applied to any mega- or meta-analytic study in which item-based behavioral measures need to be harmonized.
Electronic supplementary material
The online version of this article (doi:10.1007/s10519-014-9654-x) contains supplementary material, which is available to authorized users.
Personality; Item-Response Theory; Measurement; Genome-wide association studies; Consortium; Meta-analysis
To assess the extent to which the association between childhood sexual abuse (CSA) and early use of alcohol, cigarettes, and cannabis in adolescent girls is mediated by risk factors that tend to cluster in families where CSA occurs.
An abridged version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) was administered by telephone. Participants: 3,761 female twins aged 18–29 (14.6% African American, 85.4% European American).
CSA experiences and history of substance use were queried in the SSAGA-based interviews.
After controlling for familial influences on early substance use by including co-twin early use status in models, separate Cox proportional hazards regression analyses predicting onset of alcohol, cigarette, and cannabis use revealed a significant association with CSA. The effect was observed through age 19 for cigarettes and through age 21 for cannabis, but was limited to age 14 or younger for alcohol, with the most pronounced risk before age 10 (HR=4.59; CI: 1.96–10.74). CSA-associated risk for initiation of cigarette and cannabis use was also highest in the youngest age range, but the decline with age was much more gradual and the hazard ratios significantly lower (1.70; CI:1.13–2.56 for cigarettes and 2.34, CI:1.58–3.46 for cannabis).
Childhood sexual abuse history is a distinct risk factor for use of cigarettes and cannabis, and a very strong predictor of early age at first drink.
sexual abuse; alcohol; cigarettes; cannabis; women
Disordered gambling is a moderately heritable trait, but the underlying genetic basis is largely unknown. We performed a genome-wide association study (GWAS) for disordered gambling using a quantitative factor score in 1,312 twins from 894 Australian families. Association was conducted for 2,381,914 single nucleotide polymorphisms (SNPs) using the family-based association test in Merlin followed by gene and pathway enrichment analyses. Although no SNP reached genome-wide significance, six achieved P-values < 1 × 10−5 with variants in three genes (MT1X, ATXN1 and VLDLR) implicated in disordered gambling. Secondary case-control analyses found two SNPs on chromosome 9 (rs1106076 and rs12305135 near VLDLR) and rs10812227 near FZD10 on chromosome 12 to be significantly associated with lifetime DSM-IV pathological gambling and SOGS classified probable pathological gambling status. Furthermore, several addiction-related pathways were enriched for SNPs associated with disordered gambling. Finally, gene-based analysis of 24 candidate genes for dopamine agonist induced gambling in individuals with Parkinson’s disease suggested an enrichment of SNPs associated with disordered gambling. We report the first GWAS of disordered gambling. While further replication is required, the identification of susceptibility loci and biological pathways will be important in characterizing the biological mechanisms that underpin disordered gambling.
association; disordered gambling; genomewide; MERLIN; quantitative
Several studies have identified genes associated with alcohol use disorders, but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism (COGA) to identify novel genes affecting risk for alcohol dependence. To maximize the power of the extended family design we used a quantitative endophenotype, measured in all individuals: number of alcohol dependence symptoms endorsed (symptom count). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with symptom count were also associated with the dichotomous phenotype, DSM-IV alcohol dependence. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol (p=4.5×10−8, inflation corrected p=9.4×10−7). Results with DSM-IV alcohol dependence in the regions of interest support our findings with symptom count, though the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: non-overlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian twin-family study of alcohol use disorders (OZALC). Nominal association of C15orf53 with symptom count was observed in SAGE. The variant that showed strongest association with symptom count, rs12912251 and its highly correlated variants (D′=1, r2≥ 0.95), has previously been associated with risk for bipolar disorder.
DSM-IV alcohol dependence symptoms; Family-based GWAS; C15orf53; Quantitative traits
Approaches exploiting extremes of the trait distribution may reveal novel loci for common traits, but it is unknown whether such loci are generalizable to the general population. In a genome-wide search for loci associated with upper vs. lower 5th percentiles of body mass index, height and waist-hip ratio, as well as clinical classes of obesity including up to 263,407 European individuals, we identified four new loci (IGFBP4, H6PD, RSRC1, PPP2R2A) influencing height detected in the tails and seven new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3, ZZZ3) for clinical classes of obesity. Further, we show that there is large overlap in terms of genetic structure and distribution of variants between traits based on extremes and the general population and little etiologic heterogeneity between obesity subgroups.
Alcohol consumption has multiple biochemical consequences. Only a few of these are useful as diagnostic markers but many reflect potentially harmful or beneficial effects of alcohol. Average consumption of two to four drinks per day is associated with lower overall or cardiovascular mortality risk than either lower or higher intake. We have analysed the dose-response relationships between reported alcohol consumption and 17 biomarkers, with emphasis on intake of up to three drinks per day.
Biochemical tests were performed on serum from 8396 study participants (3750 men and 4646 women, aged 51 ± 13 years, range 18–93) who had provided information on alcohol consumption in the week preceding blood collection.
GGT, ALT, AST, CDT, urate, ferritin and bilirubin showed little or no change with alcohol consumption below two to three drinks per day, but increased with higher intake. HDL-C and albumin showed increasing results, and insulin showed decreasing results, across the entire range of alcohol use. Biphasic responses, where subjects reporting one to two drinks per day had lower results than those reporting either more or less alcohol use, occurred for triglycerides, glucose, C-reactive protein, alkaline phosphatase and butyrylcholinesterase. Increasing alcohol use was associated with decreasing LDL-C in younger women, but higher LDL-C in older men.
Some markers show threshold relationships with alcohol, others show continuous ones, and a third group show biphasic or U-shaped relationships. Overall the biochemical sequelae of low-to-moderate alcohol use are consistent with the epidemiological evidence on morbidity and mortality.
Alcohol; Biomarkers; Dose-response curve; Population study
The role of specific gut microbes in shaping body composition remains unclear. We transplanted fecal microbiota from adult female twin pairs discordant for obesity into germ-free mice fed low-fat mouse chow, as well as diets representing different levels of saturated fat and fruit and vegetable consumption typical of the USA. Increased total body and fat mass, as well as obesity-associated metabolic phenotypes were transmissible with uncultured fecal communities, and with their corresponding fecal bacterial culture collections. Co-housing mice harboring an obese twin’s microbiota (Ob) with mice containing the lean co-twin’s microbiota (Ln) prevented the development of increased body mass and obesity-associated metabolic phenotypes in Ob cagemates. Rescue correlated with invasion of specific members of Bacteroidetes from the Ln microbiota into Ob microbiota, and was diet-dependent. These findings reveal transmissible, rapid and modifiable effects of diet-by-microbiota interactions.
The genetic contribution to liability for opioid dependence is well-established; identification of the responsible genes has proved challenging.
To examine association of 1430 candidate gene single-nucleotide polymorphisms (SNPs) with heroin dependence, reporting here only the 71 SNPs in the chromosome 11 gene cluster (NCAM1, TTC12, ANKK1, DRD2) that include the strongest observed associations.
Case-control genetic association study that included two control groups (lacking an established optimal control group).
Semi-structured psychiatric interviews
Australian cases (N=1459) ascertained from opioid replacement therapy (ORT) clinics, neighborhood controls (N=531) ascertained from economically disadvantaged areas near opioid replacement therapy clinics, and unrelated Australian Twin Registry (ATR) controls (N=1495) not dependent on alcohol or illicit drugs selected from a twin and family sample.
Main Outcome Measure
Lifetime heroin dependence
Comparison of cases with Australian Twin Registry controls found minimal evidence of association for all chromosome 11 cluster SNPs (p≥.01); a similar comparison to neighborhood controls revealed greater differences (p≥1.8 × 10−4). Comparing cases (N=1459) with the subgroup of neighborhood controls not dependent on illicit drugs (N=340), three SNPs were significantly associated (correcting for multiple testing): ANKK1 SNP rs877138 [most strongly associated; odds ratio 1.59; 95%CI (1.32–1.92); p=9.7 × 10−7], ANKK1 SNP rs4938013 and TTC12 SNP rs7130431. A similar pattern of association was observed when comparing illicit drug-dependent (N=191) and non-dependent (N=340) neighborhood controls, suggesting that liability likely extends to non-opioid illicit drug dependence. Aggregate heroin dependence risk associated with two SNPs, rs877138 and rs4492854 (located in NCAM1), varied more than 4-fold (p= 2.74 × 10−9 for the risk-associated linear trend).
Our results provide further evidence of association for chromosome 11 gene cluster SNPs with substance dependence, including extension of liability to illicit drug dependence. Our findings highlight the necessity of considering drug exposure history when selecting control groups for genetic investigations of illicit drug dependence.