Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects.

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls.

Meta-analysis of Positive and Negative Symptoms Reveals Schizophrenia Modifier Genes.

Background: Evidence suggests that genetic factors may influence both schizophrenia (Scz) and its clinical presentation. In recent years, genome-wide association studies (GWAS) have demonstrated considerable success in identifying risk loci. Detection of "modifier loci" has the potential to further elucidate underlying disease processes.

Genome-wide gene pathway analysis of psychotic illness symptom dimensions based on a new schizophrenia-specific model of the OPCRIT.

Empirically derived phenotypic measurements have the potential to enhance gene-finding efforts in schizophrenia. Previous research based on factor analyses of symptoms has typically included schizoaffective cases. Deriving factor loadings from analysis of only narrowly defined schizophrenia cases could yield more sensitive factor scores for gene pathway and gene ontology analyses.

An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis.

Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls. We found association with duplications at chr20p12.

Genome-wide association analysis identifies 13 new risk loci for schizophrenia.

Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder.

Genome-wide association study of multiplex schizophrenia pedigrees.

Objective: The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs).

Method: The family sample included 2,461 individuals from 631 pedigrees (581 in the primary European-ancestry analyses). Association was tested for single SNPs and genetic pathways.

Comprehensive gene-based association study of a chromosome 20 linked region implicates novel risk loci for depressive symptoms in psychotic illness.

Background: Prior genomewide scans of schizophrenia support evidence of linkage to regions of chromosome 20. However, association analyses have yet to provide support for any etiologically relevant variants.

Methods: We analyzed 2988 LD-tagging single nucleotide polymorphisms (SNPs) in 327 genes on chromosome 20, to test for association with schizophrenia in 270 Irish high-density families (ISHDSF, N = 270 families, 1408 subjects).

Replication of association between schizophrenia and ZNF804A in the Irish Case-Control Study of Schizophrenia sample.

A recent genome-wide association study reported association between schizophrenia and the ZNF804A gene on chromosome 2q32.1. We attempted to replicate these findings in our Irish Case-Control Study of Schizophrenia (ICCSS) sample (N=1021 cases, 626 controls).

Association study of SNAP25 and schizophrenia in Irish family and case-control samples.

SNAP25 occurs on chromosome 20p12.2, which has been linked to schizophrenia in some samples, and recently linked to latent classes of psychotic illness in our sample. SNAP25 is crucial to synaptic functioning, may be involved in axonal growth and dendritic sprouting, and its expression may be decreased in schizophrenia.

The dystrobrevin binding protein 1 (DTNBP1) gene is associated with schizophrenia in the Irish Case Control Study of Schizophrenia (ICCSS) sample.

Background: DTNBP1 is associated with schizophrenia in many studies, but the associated alleles and haplotypes vary between samples.

Method: We assessed nine single nucleotide polymorphisms (SNPs) in this gene for association with schizophrenia in a new sample of 1021 cases and 626 controls from Ireland.

Results: Four SNPs give evidence of association (0.

No association of dysbindin with symptom factors of schizophrenia in an Irish case-control sample.

Robust associations between the dysbindin gene (DTNBP1) and schizophrenia have been demonstrated in many but not all samples, and evidence that this gene particularly predisposes to negative symptoms in this illness has been presented. The current study sought to replicate the previously reported negative symptom associations in an Irish case-control sample. Association between dysbindin and schizophrenia has been established in this cohort, and a factor analysis of the assessed symptoms yielded three factors, Positive, Negative, and Schneiderian.

Meta-analysis of 32 genome-wide linkage studies of schizophrenia.

A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P(SR)) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb).

Genomewide linkage scan of schizophrenia in a large multicenter pedigree sample using single nucleotide polymorphisms.

A genomewide linkage scan was carried out in eight clinical samples of informative schizophrenia families. After all quality control checks, the analysis of 707 European-ancestry families included 1615 affected and 1602 unaffected genotyped individuals, and the analysis of all 807 families included 1900 affected and 1839 unaffected individuals. Multipoint linkage analysis with correction for marker-marker linkage disequilibrium was carried out with 5861 single nucleotide polymorphisms (SNPs; Illumina version 4.

The trace amine associated receptor (TAAR6) gene is not associated with schizophrenia in the Irish Case-Control Study of Schizophrenia (ICCSS) sample.

To replicate previous association between TAAR6 and schizophrenia, including our own finding in the Irish Study of High Density Schizophrenia Families (ISHDSF) sample, we genotyped 12 single nucleotide polymorphisms (SNPs) in the Irish Case-Control Study of Schizophrenia (ICCSS) sample. Only rs9389020 provided nominal evidence for association (p<0.0228), which did not withstand the permutation testing (p<0.

Monoamine oxidase A and childhood adversity as risk factors for conduct disorder in females.

Background: Recent studies among males have reported a genotype-environment interaction (GxE) in which low-activity alleles at the monoamine oxidase A (MAOA) locus conferred greater sensitivity to the effects of childhood adversity on risk for conduct disorder (CD). So far, few studies of females have controlled for gene-environment correlation or used females heterozygous for this X-linked gene.

Method: Logistic regression analysis of a sample of 721 females ages 8-17 years from the longitudinal Virginia Twin Study of Adolescent Behavioral Development (VTSABD) assessed the additive effects of MAOA genotypes on risk for CD, together with the main effect of childhood adversity and parental antisocial personality disorder (ASP), as well as the interaction of MAOA with childhood adversity on risk for CD.

AKT1 is associated with schizophrenia across multiple symptom dimensions in the Irish study of high density schizophrenia families.

Background: The phosphatidylinositol 3-kinase (PI3K)-AKT signal transduction pathway is critical to cell growth and survival. In vitro functional studies indicate that the candidate schizophrenia susceptibility gene DTNBP1 influences AKT signaling to promote neuronal viability. The AKT1 gene has also been implicated in schizophrenia by association studies and decreased protein expression in the brains of schizophrenic patients.

A region of 35 kb containing the trace amine associate receptor 6 (TAAR6) gene is associated with schizophrenia in the Irish study of high-density schizophrenia families.

The TAAR6 gene has been previously associated with schizophrenia in 192 pedigrees of European and African ancestry. To replicate these findings we performed an association study of TAAR6 in 265 pedigrees of the Irish Study of High-Density Schizophrenia Families (ISHDSF). Of the 24 genotyped single-nucleotide polymorphisms only rs12189813 and rs9389011 provided single-marker evidence for association (0.

Alcohol dependence is associated with the ZNF699 gene, a human locus related to Drosophila hangover, in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD) sample.

Because tolerance is an important aspect of alcohol dependence (AD) in humans, recent evidence showing that the Drosophila gene hang is critically involved in the development of alcohol tolerance in the fly suggests that variation in related human loci might be important in the etiology of alcohol-related disorders. The orthology of hang in mammals is complex, but a number of human gene products (including ZNF699) with similar levels of amino-acid identity (18-26%) and similarity (30-41%), are consistently identified as the best matches with the translated hang sequence. We tested for association between the dichotomous clinical phenotype of alcohol dependence and seven single nucleotide polymorphisms (SNPs) in ZNF699 in our sample of 565 genetically independent cases and 496 siblings diagnosed with AD, and 609 controls.

Childhood adversity, monoamine oxidase a genotype, and risk for conduct disorder.

Background: Very little is known about how different sets of risk factors interact to influence risk for psychiatric disorder.

Objective: To replicate a recent report of a genotype-environment interaction that predicts risk for antisocial behavior in boys.

Design: Characterizing risk for conduct disorder in boys in association with monoamine oxidase A genotype and exposure to familial adversity, defined by interparental violence, parental neglect, and inconsistent discipline.

Multicenter linkage study of schizophrenia loci on chromosome 22q.

The hypothesis of the existence of one or more schizophrenia susceptibility loci on chromosome 22q is supported by reports of genetic linkage and association, meta-analyses of linkage, and the observation of elevated risk for psychosis in people with velocardiofacial syndrome, caused by 22q11 microdeletions. We tested this hypothesis by evaluating 10 microsatellite markers spanning 22q in a multicenter sample of 779 pedigrees. We also incorporated age at onset and sex into the analysis as covariates.

Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes.

From our linkage study of Irish families with a high density of schizophrenia, we have previously reported evidence for susceptibility genes in regions 5q21-31, 6p24-21, 8p22-21, and 10p15-p11. In this report, we describe the cumulative results from independent genome scans of three a priori random subsets of 90 families each, and from multipoint analysis of all 270 families in ten regions. Of these ten regions, three (13q32, 18p11-q11, and 18q22-23) did not generate scores above the empirical baseline pairwise scan results, and one (6q13-26) generated a weak signal.

Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia.

Prior evidence has supported the existence of multiple susceptibility genes for schizophrenia. Multipoint linkage analysis of the 270 Irish high-density pedigrees that we have studied, as well as results from several other samples, suggest that at least one such gene is located in region 6p24-21. In the present study, family-based association analysis of 36 simple sequence-length-polymorphism markers and of 17 SNP markers implicated two regions, separated by approximately 7 Mb.

No major schizophrenia locus detected on chromosome 1q in a large multicenter sample.

Reports of substantial evidence for genetic linkage of schizophrenia to chromosome 1q were evaluated by genotyping 16 DNA markers across 107 centimorgans of this chromosome in a multicenter sample of 779 informative schizophrenia pedigrees. No significant evidence was observed for such linkage, nor for heterogeneity in allele sharing among the eight individual samples. Separate analyses of European-origin families, recessive models of inheritance, and families with larger numbers of affected cases also failed to produce significant evidence for linkage.

An association study of DRD5 with smoking initiation and progression to nicotine dependence.

A large body of genetic epidemiological data strongly implicate genetic factors in the etiology of smoking behavior. Polymorphisms of genes in the dopaminergic system are plausible functional candidate genes and a linkage and an association study suggested that the type 5 dopamine receptor gene (DRD5) may be etiologically involved. We investigated the association of four DRD5 polymorphisms with smoking initiation and progression to nicotine dependence in a population-based sample of over 900 subjects.