Highlights d Three groups of highly genetically-related disorders among 8 psychiatric disorders d Identified 109 pleiotropic loci affecting more than one disorder d Pleiotropic genes show heightened expression beginning in 2 nd prenatal trimester d Pleiotropic genes play prominent roles in neurodevelopmental processes Authors Cross-Disorder Group of the Psychiatric Genomics Consortium

SummaryTourette's syndrome is a common developmental neuropsychiatric disorder characterized by chronic motor and vocal tics. Despite a strong genetic contribution, inheritance is complex, and risk alleles have proven difficult to identify. Here, we describe an analysis of linkage in a two-generation pedigree leading to the identification of a rare functional mutation in the HDC gene encoding Lhistidine decarboxylase, the rate-limiting enzyme in histamine biosynthesis. Our findings, together with previously published data from model systems, point to a role for histaminergic neurotransmission in the mechanism and modulation of Tourette's syndrome and tics.Tourette's Syndrome is Characterized by Childhood Onset, Waxing and waning symptomatology, and typically, improvement in adulthood. The molecular underpinnings of the disorder remain uncertain, although multiple lines of evidence suggest involvement of dopaminergic neurotransmission and abnormalities involving cortical-striatal-thalamiccortical circuitry. 1 Current treatment focuses on tic reduction and management of prevalent coexisting conditions such as obsessive-compulsive disorder and attention deficithyperactivity disorder. However, therapeutic options have limited efficacy and may carry clinically significant side effects. Consequently, the development of new treatments based on an improved understanding of disease pathophysiology is a high priority. 2 The large genetic contribution to Tourette's syndrome is well established. 3 4,5 However, mutations are found in only a small proportion of affected persons, and the protein's normal function and the manner in which it may contribute to Tourette's syndrome are not yet well understood.In light of the probable genetic heterogeneity underlying Tourette's syndrome, we sought families in which the syndrome is transmitted in a mendelian fashion, which is rare. As has been shown for other complex disorders, gene discovery in such families may help to uncover molecular mechanisms of disease. 6 MethodsMethods are described briefly here; for complete details, see the Supplementary Appendix, available with the full text of this article at NEJM.org. All studies were approved by the Yale Institutional Review Board, and all participants provided written informed consent.A nonconsanguineous two-generation pedigree was referred to our laboratory (Fig. 1). The father and all eight offspring met the criteria for Tourette's syndrome in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (Table S1 in the Supplementary Appendix). Two children and the father also have obsessive-compulsive disorder. The mother, her parents, and her extended family are reportedly free from Tourette's syndrome, chronic tics, and obsessive-compulsive disorder.DNA samples from all family members in the two-generation pedigree were genotyped by means of Affymetrix GeneChip Human Mapping 100K Arrays and short-tandem-repeat markers that had been identified within the lod -2 linkage interval (the equivalent of a conf...

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.

Background THAP1 was recently identified as the gene causing DYT6 primary dystonia; a founder mutation was detected in Amish–Mennonite families and a different mutation identified in an additional family. To determine the role of this gene more broadly, we screened for mutations in early-onset primary dystonia families with diverse ancestries. Methods We identified 36 non-DYT1 multiplex families in which at least one individual had non-focal involvement and onset <22 years. All THAP1 coding exons were sequenced. Clinical features of those with DYT6 mutations were compared to mutation negative individuals and genotype-phenotype differences assessed. Findings Nine of 36 families (25%) harbored mutations and most were of German, Irish or Italian ancestry. One had the Amish-Mennonite founder mutation, while the remaining 8 families each harbored unique truncating or missense mutations. Clinical features in families with mutations conformed to the previously described DYT6 phenotype; age–onset, however, extended to 49 years. Compared to non-carriers, mutation carriers were younger at onset; their dystonia was more likely to begin in brachial, and not cervical, muscles and was more likely to become generalized including speech involvement. Genotype–phenotype differences were not found. Interpretation THAP1 mutations underlie a substantial proportion of early-onset primary dystonia in non-DYT1 families of differing European ancestry. Characteristic clinical features include involvement of both limb and cranial muscles and speech is often affected.