A. C. Heath

Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo

Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435u2009291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 signals localized to a 167u2009kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain) with P-values of 7.7 × 10−7 for rs2715148 and 1.2 × 10−6 for rs2522833. We undertook replication of SNPs in this region in five independent samples (6079 MDD independent cases and 5893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded P=6.4 × 10−8 for the nonsynonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.

Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned

Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls and >1u2009M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.

Meta-analysis of genome-wide association studies for personality

Personality can be thought of as a set of characteristics that influence peoples thoughts, feelings and behavior across a variety of settings. Variation in personality is predictive of many outcomes in life, including mental health. Here we report on a meta-analysis of genome-wide association (GWA) data for personality in 10 discovery samples (17u2009375 adults) and five in silico replication samples (3294 adults). All participants were of European ancestry. Personality scores for Neuroticism, Extraversion, Openness to Experience, Agreeableness and Conscientiousness were based on the NEO Five-Factor Inventory. Genotype data of ∼2.4M single-nucleotide polymorphisms (SNPs; directly typed and imputed using HapMap data) were available. In the discovery samples, classical association analyses were performed under an additive model followed by meta-analysis using the weighted inverse variance method. Results showed genome-wide significance for Openness to Experience near the RASA1 gene on 5q14.3 (rs1477268 and rs2032794, P=2.8 × 10−8 and 3.1 × 10−8) and for Conscientiousness in the brain-expressed KATNAL2 gene on 18q21.1 (rs2576037, P=4.9 × 10−8). We further conducted a gene-based test that confirmed the association of KATNAL2 to Conscientiousness. In silico replication did not, however, show significant associations of the top SNPs with Openness and Conscientiousness, although the direction of effect of the KATNAL2 SNP on Conscientiousness was consistent in all replication samples. Larger scale GWA studies and alternative approaches are required for confirmation of KATNAL2 as a novel gene affecting Conscientiousness.

Genetic and environmental contributions to cannabis dependence in a national young adult twin sample

BACKGROUNDnThis paper examines genetic and environmental contributions to risk of cannabis dependence.nnnMETHODnSymptoms of cannabis dependence and measures of social, family and individual risk factors were assessed in a sample of 6265 young adult male and female Australian twins born 1964-1971.nnnRESULTSnSymptoms of cannabis dependence were common: 11.0% of sample (15.1% of men and 7.8% of women) reported two or more symptoms of dependence. Correlates of cannabis dependence included educational attainment, exposure to parental conflict, sexual abuse, major depression, social anxiety and childhood conduct disorder. However, even after control for the effects of these factors, there was evidence of significant genetic effects on risk of cannabis dependence. Standard genetic modelling indicated that 44.7% (95% CI = 15-72.2) of the variance in liability to cannabis dependence could be accounted for by genetic factors, 20.1% (95% CI = 0-43.6) could be attributed to shared environment factors and 35.3% (95% CI = 26.4-45.7) could be attributed to non-shared environmental factors. However, while there was no evidence of significant gender differences in the magnitude of genetic and environmental influences, a model which assumed both genetic and shared environmental influences on risks of cannabis dependence among men and shared environmental but no genetic influences among women provided an equally good fit to the data.nnnCONCLUSIONSnThere was consistent evidence that genetic risk factors are important determinants of risk of cannabis dependence among men. However, it remains uncertain whether there are genetic influences on liability to cannabis dependence among women.

Genetic and Environmental Contributions to Variance in Age at First Sexual Intercourse

Little is known about the relative importance of genetic and environmental factors as determinants of age at first sexual intercourse In this study, subjects were 5,080 individuals from the Australian Twin Registry (3,310 females, I 770 males, age range 27-70 years, median 40 years) who completed a semistructured interview by telephone in 1992-1993 Self-reported age at first intercourse correlated higher for identical (monozygotic) twins than for nonidentical (dizygotic) twins Structural equation model fitting found that the genetic contribution to variance was considerably greater among twins aged 40 years or less (72% for males and 49% for females) than for those aged from 41 to 70 years (0% for males and 32% for females) Among the older cohort, there was evidence that somewhat different aspects of the shared social environment influenced age at onset in males and females In a more laissez-faire social climate in recent decades, it is likely that biological and psychological characteristics that are partly under genetic control significantly influence the age at which a person commences sexual activity

Social phobia in a population-based female adolescent twin sample: co-morbidity and associated suicide-related symptoms

BACKGROUNDnThis report attempted to replicate and extend prior work examining social phobia (SP), co-morbid psychiatric illnesses, and the risk of suicidal ideation and suicide attempts incurred by their adolescent sufferers.nnnMETHODSnSP, alcohol dependence (ALD) and major depressive disorder (MDD) diagnoses, and suicide-related symptoms, were assessed in a population-based adolescent female twin sample. The differentiation of risks as a function of co-morbidity was explored. A trivariate model was fitted to estimate sharing of genetic and environmental vulnerability between SP and co-morbid disorders.nnnRESULTSnThe lifetime prevalence of SP was 16.3 %. Significant risk for co-morbid MDD (OR = 3.2) and ALD (OR = 2.1) was observed. Strong evidence for shared genetic vulnerability between SP and MDD (respective heritabilities 28%, 45%; genetic r = 1.0) was observed with moderate support noted for similar sharing between SP and ALD (genetic r = 0.52, heritability for ALD 63%). SP with co-morbid MDD was associated with elevated risk for ALD and for suicide-related symptoms.nnnCONCLUSIONSnSP is a common illness often followed by co-morbid MDD and ALD. SP with comorbid MDD predicts a substantially elevated risk of ALD and suicide-related symptoms, stressing the need for early SP detection.

The genetics of addiction—a translational perspective

Addictions are serious and common psychiatric disorders, and are among the leading contributors to preventable death. This selective review outlines and highlights the need for a multi-method translational approach to genetic studies of these important conditions, including both licit (alcohol, nicotine) and illicit (cannabis, cocaine, opiates) drug addictions and the behavioral addiction of disordered gambling. First, we review existing knowledge from twin studies that indicates both the substantial heritability of substance-specific addictions and the genetic overlap across addiction to different substances. Next, we discuss the limited number of candidate genes which have shown consistent replication, and the implications of emerging genomewide association findings for the genetic architecture of addictions. Finally, we review the utility of extensions to existing methods such as novel phenotyping, including the use of endophenotypes, biomarkers and neuroimaging outcomes; emerging methods for identifying alternative sources of genetic variation and accompanying statistical methodologies to interpret them; the role of gene–environment interplay; and importantly, the potential role of genetic variation in suggesting new alternatives for treatment of addictions.Addictions are serious and common psychiatric disorders, and are among the leading contributors to preventable death. This selective review outlines and highlights the need for a multi-method translational approach to genetic studies of these important conditions, including both licit (alcohol, nicotine) and illicit (cannabis, cocaine, opiates) drug addictions and the behavioral addiction of disordered gambling. First, we review existing knowledge from twin studies that indicates both the substantial heritability of substance-specific addictions and the genetic overlap across addiction to different substances. Next, we discuss the limited number of candidate genes which have shown consistent replication, and the implications of emerging genomewide association findings for the genetic architecture of addictions. Finally, we review the utility of extensions to existing methods such as novel phenotyping, including the use of endophenotypes, biomarkers and neuroimaging outcomes; emerging methods for identifying alternative sources of genetic variation and accompanying statistical methodologies to interpret them; the role of gene–environment interplay; and importantly, the potential role of genetic variation in suggesting new alternatives for treatment of addictions.

Monoamine oxidase: associations with alcohol dependence, smoking and other measures of psychopathology.

BACKGROUNDnMany reports have appeared on associations between platelet monoamine oxidase (MAO) activity and susceptibility to psychiatric conditions; principally alcohol dependence but also conduct disorder, other drug use and depression. Recently, it has become apparent that MAO activity is inhibited by some component of cigarette smoke, and smokers have low platelet MAO activity. Since the prevalence of smoking is higher in many of the conditions in which MAO has been implicated, the MAO susceptibility associations may be partly, or entirely, false.nnnMETHODSnWe have measured platelet MAO in 1551 subjects, recruited from the Australian NHMRC Twin Registry, who have provided information on alcohol use and dependence, smoking, conduct disorder, depression, attempted suicide, panic disorder and social phobia.nnnRESULTSnCurrent smoking reduced platelet MAO activity in a significant and dose-related manner, with no evidence of lower MAO in ex-smokers or in non-smoking subjects with co-twins who smoked. Alcohol use and lifetime DSM-III-R alcohol dependence history were not associated with MAO activity when smoking was taken into account. Depression, panic disorder and social phobia showed no significant associations with platelet MAO activity. Subjects with a history of serious attempts at suicide had low platelet MAO activity; but although the difference from controls was as great as the reduction associated with smoking it was not significant after correction for smoking effects.nnnCONCLUSIONSnAlthough synaptic MAO activity undoubtedly plays a role in psychopathology, the concept that platelet MAO activity is a direct genetic marker of vulnerability to alcohol dependence cannot be sustained.

Genetic influences on post-natal depressive symptoms: findings from an Australian twin sample

BACKGROUNDnConflicting evidence exists on causes of vulnerability to post-natal depression. We investigated genetic and environmental influences on variation in post-natal depressive symptoms (PNDS) following first live birth, and sources of covariation with the personality trait Neuroticism and lifetime major depression occurring post-natally (DEP-PN) and at other times (DEP-XPN) to test for shared genetic influences.nnnMETHODnRetrospective interview and questionnaire data from 838 parous female twin pairs (539 monozygotic, 299 dizygotic) from the Australian National Health and Medical Research Council volunteer adult twin register were used for multivariate genetic model-fitting. Data on PNDS were evaluated for consistency with diagnostic interview assessment.nnnRESULTSnGenetic factors explained 38% of variance in PNDS (95% confidence interval 26-49%) and 25% of the variance in interview-assessed DEP-PN. The genetic correlation between PNDS and lifetime major depression (DEP-PN and DEP-XPN) was low (r(g) = 0.17, 95% confidence interval = 0.09-0.28), suggesting that the questionnaire was measuring a construct other than postnatally occurring major depression, possibly post-natal dysphoria. Associations between PNDS and obstetric factors were very modest.nnnCONCLUSIONSnFindings suggest modest genetic influences on major depression occurring postnatally. Independent and stronger genetic influences identified for post-natal symptomatology or dysphoria (PNDS) justify further investigation.

The genetic association between personality and major depression or bipolar disorder. A polygenic score analysis using genome-wide association data

The relationship between major depressive disorder (MDD) and bipolar disorder (BD) remains controversial. Previous research has reported differences and similarities in risk factors for MDD and BD, such as predisposing personality traits. For example, high neuroticism is related to both disorders, whereas openness to experience is specific for BD. This study examined the genetic association between personality and MDD and BD by applying polygenic scores for neuroticism, extraversion, openness to experience, agreeableness and conscientiousness to both disorders. Polygenic scores reflect the weighted sum of multiple single-nucleotide polymorphism alleles associated with the trait for an individual and were based on a meta-analysis of genome-wide association studies for personality traits including 13u2009835 subjects. Polygenic scores were tested for MDD in the combined Genetic Association Information Network (GAIN-MDD) and MDD2000+ samples (N=8921) and for BD in the combined Systematic Treatment Enhancement Program for Bipolar Disorder and Wellcome Trust Case–Control Consortium samples (N=6329) using logistic regression analyses. At the phenotypic level, personality dimensions were associated with MDD and BD. Polygenic neuroticism scores were significantly positively associated with MDD, whereas polygenic extraversion scores were significantly positively associated with BD. The explained variance of MDD and BD, ∼0.1%, was highly comparable to the variance explained by the polygenic personality scores in the corresponding personality traits themselves (between 0.1 and 0.4%). This indicates that the proportions of variance explained in mood disorders are at the upper limit of what could have been expected. This study suggests shared genetic risk factors for neuroticism and MDD on the one hand and for extraversion and BD on the other.