Polygenic risk score and heritability estimates reveals a genetic relationship between ASD and OCD.

Obsessive-compulsive disorder (OCD) and Autism spectrum disorder (ASD) are both highly heritable neurodevelopmental disorders that conceivably share genetic risk factors. However, the underlying genetic determinants remain largely unknown. In this work, the authors describe a combined genome-wide association study (GWAS) of ASD and OCD. The OCD dataset includes 2998 individuals in nuclear families. The ASD dataset includes 6898 individuals in case-parents trios. GWAS summary statistics were examined for potential enrichment of functional variants associated with gene expression levels in brain regions. The top ranked SNP is rs4785741 (chromosome 16) with P value=6.9×10-7 in our re-analysis. Polygenic risk score analyses were conducted to investigate the genetic relationship within and across the two disorders. These analyses identified a significant polygenic component of ASD, predicting 0.11% of the phenotypic variance in an independent OCD data set. In addition, we examined the genomic architecture of ASD and OCD by estimating heritability on different chromosomes and different allele frequencies, analyzing genome-wide common variant data by using the Genome-wide Complex Trait Analysis (GCTA) program. The estimated global heritability of OCD is 0.427 (se=0.093) and 0.174 (se=0.053) for ASD in these imputed data.

Whole-genome association analysis of treatment response in obsessive-compulsive disorder.

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10(-5)) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10(-6) and 8.41 × 10(-6), respectively. The other 35 variations with signals of potential significance (P<10(-4)) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed.

Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS.

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples.

Is obsessive-compulsive disorder an anxiety disorder, and what, if any, are spectrum conditions? A family study perspective.

BACKGROUND: Experts have proposed removing obsessive-compulsive disorder (OCD) from the anxiety disorders section and grouping it with putatively related conditions in DSM-5. The current study uses co-morbidity and familiality data to inform these issues. METHOD: Case family data from the OCD Collaborative Genetics Study (382 OCD-affected probands and 974 of their first-degree relatives) were compared with control family data from the Johns Hopkins OCD Family Study (73 non-OCD-affected probands and 233 of their first-degree relatives). RESULTS: Anxiety disorders (especially agoraphobia and generalized anxiety disorder), cluster C personality disorders (especially obsessive-compulsive and avoidant), tic disorders, somatoform disorders (hypochondriasis and body dysmorphic disorder), grooming disorders (especially trichotillomania and pathological skin picking) and mood disorders (especially unipolar depressive disorders) were more common in case than control probands; however, the prevalences of eating disorders (anorexia and bulimia nervosa), other impulse-control disorders (pathological gambling, pyromania, kleptomania) and substance dependence (alcohol or drug) did not differ between the groups. The same general pattern was evident in relatives of case versus control probands. Results in relatives did not differ markedly when adjusted for demographic variables and proband diagnosis of the same disorder, though the strength of associations was lower when adjusted for OCD in relatives. Nevertheless, several anxiety, depressive and putative OCD-related conditions remained significantly more common in case than control relatives when adjusting for all of these variables simultaneously. CONCLUSIONS: On the basis of co-morbidity and familiality, OCD appears related both to anxiety disorders and to some conditions currently classified in other sections of DSM-IV.

Hoarding in obsessive compulsive disorder: results from a case-control study.

Hoarding occurs relatively frequently in obsessive-compulsive disorder (OCD), and there is evidence that patients with hoarding symptoms have more severe OCD and are less responsive to treatment. In the present study, we investigated hoarding symptoms in 126 subjects with OCD. Nearly 30% of the subjects had hoarding symptoms; hoarding was twice as prevalent in males than females. Compared to the 90 non-hoarding subjects, the 36 hoarding individuals had an earlier age at onset of, and more severe, obsessive-compulsive symptoms. Hoarders had greater prevalences of symmetry obsessions, counting compulsions, and ordering compulsions. Hoarders also had greater prevalences of social phobia, personality disorders, and pathological grooming behaviors (skin picking, nail biting, and trichotillomania). Hoarding and tics were more frequent in first-degree relatives of hoarding than non-hoarding probands. The findings suggest that the treatment of OCD patients with hoarding symptoms may be complicated by more severe OCD and the presence of co-occurring disorders. Hoarding appears to be transmitted in some OCD families and may differentiate a clinical subgroup of OCD.

Personality disorders and normal personality dimensions in obsessive-compulsive disorder.

BACKGROUND: Little is known about personality disorders and normal personality dimensions in relatives of patients with obsessive-compulsive disorder (OCD). AIMS: To determine whether specific personality characteristics are part of a familial spectrum of OCD. METHOD: Clinicians evaluated personality disorders in 72 OCD case and 72 control probands and 198 case and 207 control first-degree relatives. The selfcompleted Revised NEO Personality Inventory was used for assessment of normal personality dimensions. The prevalence of personality disorders and scores on normal personality dimensions were compared between case and control probands and between case and control relatives. RESULTS: Case probands and case relatives had a high prevalence of obsessive-compulsive personality disorder (OCPD) and high neuroticism scores. Neuroticism was associated with OCPD in case but not control relatives. CONCLUSIONS: Neuroticism and OCPD may share a common familial aetiology with OCD.

The relationship of obsessive-compulsive disorder to possible spectrum disorders: results from a family study.

BACKGROUND: The familial relationship between obsessive-compulsive disorder (OCD) and "obsessive-compulsive spectrum" disorders is unclear. This study investigates the relationship of OCD to somatoform disorders (body dysmorphic disorder [BDD] and hypochondriasis), eating disorders (e.g., anorexia nervosa and bulimia nervosa), pathologic "grooming" conditions (e.g., nail biting, skin picking, trichotillomania), and other impulse control disorders (e.g., kleptomania, pathologic gambling, pyromania) using blinded family study methodology. METHODS: Eighty case and 73 control probands, as well as 343 case and 300 control first-degree relatives, were examined by psychiatrists or Ph.D. psychologists using the Schedule for Affective Disorders and Schizophrenia-Lifetime Anxiety version. Two experienced psychiatrists independently reviewed all diagnostic information and made final consensus diagnoses using DSM-IV criteria. RESULTS: Body dysmorphic disorder, hypochondriasis, any eating disorder, and any grooming condition occurred more frequently in case probands. In addition, BDD, either somatoform disorder, and any grooming condition occurred more frequently in case relatives, whether or not case probands also had the same diagnosis. CONCLUSIONS: These findings indicate that certain somatoform and pathologic grooming conditions are part of the familial OCD spectrum. Though other "spectrum" conditions may resemble OCD, they do not appear to be important parts of the familial spectrum.