Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17–29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn’s disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

Objective Although twin and family studies have shown Attention Deficit/Hyperactivity Disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association scans (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. Method We used data from four projects: a) the Children’s Hospital of Philadelphia (CHOP), b) phase I of the International Multicenter ADHD Genetics project (IMAGE), c) phase II of IMAGE (IMAGE II), and d) the Pfizer funded study from the University of California, Los Angeles, Washington University and the Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases and 2,455 controls. For each study, we imputed HapMap SNPs, computed association test statistics and transformed them to Z-scores, and then combined weighted Z-scores in a meta-analysis. Results No genome-wide significant associations were found, although an analysis of candidate genes suggests they may be involved in the disorder. Conclusions Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g. rare ones, account for much of the disorder’s heritability.

Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.

Objective-To examine gender and age differences in Attention-Deficit/Hyperactivity Disorder (ADHD) symptom endorsement in a large community-based sample.Method-Families with four or more full siblings ascertained from Missouri birth records completed telephone interviews regarding lifetime DSM-IV ADHD symptoms and the Strengths and Weaknesses of ADHD-Symptoms and Normal-behavior (SWAN) questionnaire for current ADHD symptoms. Complete data were available for 9380 subjects aged 7 to 29 years. Lifetime and current DSM-IV-like ADHD diagnoses were assigned by the DSM-IV symptom criterion. Linear regression was used to examine sex and age effects on SWAN ADHD symptom scores. Logistic regression was used to examine sex and age effects on specific ADHD diagnoses. Fractional polynomial graphs were used to examine ADHD symptom count variations across age.Results-Overall prevalence of current DSM-IV-like ADHD was 9.2% with a male:female ratio of 2.28:1. The prevalence of DSM-IV-like ADHD was highest in children. Gender differences in DSM-IV-like ADHD subtype prevalences were highest in adolescents. On average, individuals with lifetime DSM-IV-like ADHD diagnoses had elevated current ADHD symptoms even as adolescents or adults.Conclusions-Lower male:female ratios than reported in some clinic-based studies suggest that females are under-diagnosed in the community. Although they may no longer meet the full symptom criterion, young adults with a history of lifetime DSM-IV-like ADHD maintain higher levels of ADHD symptoms compared to the general population. The use of age-specific diagnostic criteria should be considered for DSM-V and ICD-11.

Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10−9). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10−6). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ~10% of the cases (P = 4.38 × 10−10) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.

"Contributions of parental alcoholism, prenatal substance exposure, and genetic transmission to child ADHD risk : A female twin study." Psychological Medicine. 35,5. 625-635. (2005 Contributions of parental alcoholism, prenatal substance exposure, and genetic transmission to child ADHD risk : a female twin study ABSTRACTBackground. Genetic influences have been shown to play a major role in determining the risk of attention-deficit hyperactivity disorder (ADHD). In addition, prenatal exposure to nicotine and/or alcohol has also been suggested to increase risk of the disorder. Little attention, however, has been directed to investigating the roles of genetic transmission and prenatal exposure simultaneously.

In this letter we describe novel, preliminary work, examining a possible mechanism of the Gene-environment interactions thought to moderate the response of individuals to stressful life events. The molecular mechanisms through which this moderation may be accomplished are currently unknown but some have suggested DNA methylation (Lui and others, 1997; McGowan and others 2009). In order to test this hypothesis, we analyzed the relationship of child abuse to methylation of cytosine residues in the promoter region of the serotonin transporter gene in DNA from 96 male and 96 female subjects from the Iowa Adoptee Studies using a principal components analysis. The results from this preliminary work suggest a lasting effect of child abuse on overall methylation levels in both males and females.It is commonly appreciated that complex behavioral illnesses result from the interplay of genetic and environmental factors. Over the past several years, large, systematic case and control studies have made significant inroads into the role of DNA sequence variation into psychiatric syndromes such as Major Depression and Schizophrenia (Boomsma and others 2008; O'Donovan and others 2008a; O'Donovan and others 2008b). These cross sectional studies indicate that the contribution of any one genetic variant to behavioral illness is limited and suggest that other factors such as epigenetic effects may play a more prominent role in disease pathology than previously thought (Neale and Purcell 2008).In humans, methylation of the 5' carbon of cytosine-guanosine dinucleotide pairs (CpG) is the predominant, almost exclusive, form of DNA methylation. Although its exact effect is contextually dependent, methylation of CpG residues in CpG "islands" (areas of increased CpG residue frequency) in the promoter regions of genes is strongly associated with attenuation of mRNA expression from that locus. Hence, CpG methylation could serve as a mechanism for the cellular fine-tuning of gene expression in response to extracellular events such as changes in diet, exposure to hormones or chemical stress. In contrast, less attention has been paid to how adverse family environments may affect epigenetic processes, and ultimately differential gene-expression. If psychosocial stressors do affect the intracellular millieu, measuring the extent of DNA methylation would allow a more precise definition of how environmental risk mechanisms contribute to key outcomes of psychiatric interest.

Comorbidity between cannabis dependence and MDD likely arises through shared genetic and environmental vulnerabilities predisposing to both outcomes. In contrast, associations between cannabis dependence and suicidal behaviors cannot be entirely explained by common predisposing genetic and/or shared environmental predispositions. Previously reported associations between early-onset cannabis use and subsequent MDD likely reflect shared genetic and environmental vulnerabilities, although it remains possible that early-onset cannabis use may predispose to suicide attempt.