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Pathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays.

ABSTRACT: Individually rare, large copy number variants (CNVs) contribute to genetic vulnerability for schizophrenia. Unresolved questions remain, however, regarding the anticipated yield of clinical microarray testing in schizophrenia. Using high-resolution genome-wide microarrays and rigorous methods, we investigated rare CNVs in a prospectively recruited community-based cohort of 459 unrelated adults with schizophrenia and estimated the minimum prevalence of clinically significant CNVs that would be detectable on a clinical microarray. A blinded review by two independent clinical cytogenetic laboratory directors of all large (>500 kb) rare CNVs in cases and well-matched controls showed that those deemed to be clinically significant were highly enriched in schizophrenia (16.4-fold increase, P < 0.0001). In a single community catchment area, the prevalence of individuals with these CNVs was 8.1%. Rare 1.7 Mb CNVs at 2q13 were found to be significantly associated with schizophrenia for the first time, compared with the prevalence in 23 838 population-based controls (42.9-fold increase, P = 0.0002). Additional novel findings that will facilitate the future clinical interpretation of smaller CNVs in schizophrenia include: (i) a greater proportion of individuals with two or more rare exonic CNVs >10 kb in size (1.5-fold increase, P = 0.0109) in schizophrenia; (ii) the systematic discovery of new candidate genes for schizophrenia; and, (iii) functional gene enrichment mapping highlighting a differential impact in schizophrenia of rare exonic deletions involving diverse functions, including neurodevelopmental and synaptic processes (4.7-fold increase, P = 0.0060). These findings suggest consideration of a potential role for clinical microarray testing in schizophrenia, as is now the suggested standard of care for related developmental disorders like autism.

SUBMITTER: Costain G

PROVIDER: S-EPMC3889806 | biostudies-other | 2013 Nov

REPOSITORIES: biostudies-other

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Pathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays.

Costain Gregory G Lionel Anath C AC Merico Daniele D Forsythe Pamela P Russell Kathryn K Lowther Chelsea C Yuen Tracy T Husted Janice J Stavropoulos Dimitri J DJ Speevak Marsha M Chow Eva W C EW Marshall Christian R CR Scherer Stephen W SW Bassett Anne S AS

Human molecular genetics 20130627 22

Individually rare, large copy number variants (CNVs) contribute to genetic vulnerability for schizophrenia. Unresolved questions remain, however, regarding the anticipated yield of clinical microarray testing in schizophrenia. Using high-resolution genome-wide microarrays and rigorous methods, we investigated rare CNVs in a prospectively recruited community-based cohort of 459 unrelated adults with schizophrenia and estimated the minimum prevalence of clinically significant CNVs that would be de ...[more]

PMID: 23813976

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Project description:Copy number variations (CNVs) can contribute to variable degrees of fitness and/or disease predisposition. Recent studies show that at least 1% of any given genome is copy number variable when compared to the human reference sequence assembly. Homozygous deletions (or CNV nulls) that are found in the normal population are of particular interest because they may serve to define non-essential genes in human biology.In a genomic screen investigating CNV in Autism Spectrum Disorders (ASDs) we detected a heterozygous deletion on chromosome 10p12.1, spanning the Patched-domain containing 3 (PTCHD3) gene, at a frequency of ~1.4% (6/427). This finding seemed interesting, given recent discoveries on the role of another Patched-domain containing gene (PTCHD1) in ASD. Screening of another 177 ASD probands yielded two additional heterozygous deletions bringing the frequency to 1.3% (8/604). The deletion was found at a frequency of ~0.73% (27/3,695) in combined control population from North America and Northern Europe predominately of European ancestry. Screening of the human genome diversity panel (HGDP-CEPH) covering worldwide populations yielded deletions in 7/1,043 unrelated individuals and those detected were confined to individuals of European/Mediterranean/Middle Eastern ancestry. Breakpoint mapping yielded an identical 102,624 bp deletion in all cases and controls tested, suggesting a common ancestral event. Interestingly, this CNV occurs at a break of synteny between humans and mouse. Considering all data, however, no significant association of these rare PTCHD3 deletions with ASD was observed. Notwithstanding, our RNA expression studies detected PTCHD3 in several tissues, and a novel shorter isoform for PTCHD3 was characterized. Expression in transfected COS-7 cells showed PTCHD3 isoforms colocalize with calnexin in the endoplasmic reticulum. The presence of a patched (Ptc) domain suggested a role for PTCHD3 in various biological processes mediated through the Hedgehog (Hh) signaling pathway. However, further investigation yielded one individual harboring a homozygous deletion (PTCHD3 null) without ASD or any other overt abnormal phenotype. Exon sequencing of PTCHD3 in other individuals with deletions revealed compound point mutations also resulting in a null state.Our data suggests that PTCHD3 may be a non-essential gene in some humans and characterization of this novel CNV at 10p12.1 will facilitate population and disease studies.

Project description:Endometriosis is a complex gynecological condition that affects 6-10% of women in their reproductive years and is defined by the presence of endometrial glands and stroma outside the uterus. Twin, family, and genome-wide association (GWA) studies have confirmed a genetic role, yet only a small part of the genetic risk can be explained by SNP variation. Copy number variants (CNVs) account for a greater portion of human genetic variation than SNPs and include more recent mutations of large effect. CNVs, likely to be prominent in conditions with decreased reproductive fitness, have not previously been examined as a genetic contributor to endometriosis. Here we employ a high-density genotyping microarray in a genome-wide survey of CNVs in a case-control population that includes 2,126 surgically confirmed endometriosis cases and 17,974 population controls of European ancestry. We apply stringent quality filters to reduce the false positive rate common to many CNV-detection algorithms from 77.7% to 7.3% without noticeable reduction in the true positive rate. We detected no differences in the CNV landscape between cases and controls on the global level which showed an average of 1.92 CNVs per individual with an average size of 142.3 kb. On the local level we identify 22 CNV-regions at the nominal significance threshold (P<0.05), which is greater than the 8.15 CNV-regions expected based on permutation analysis (P<0.001). Three CNV's passed a genome-wide P-value threshold of 9.3 × 10(-4); a deletion at SGCZ on 8p22 (P = 7.3 × 10(-4), OR = 8.5, Cl = 2.3-31.7), a deletion in MALRD1 on 10p12.31 (P = 5.6 × 10(-4), OR = 14.1, Cl = 2.7-90.9), and a deletion at 11q14.1 (P = 5.7 × 10(-4), OR = 33.8, Cl = 3.3-1651). Two SNPs within the 22 CNVRs show significant genotypic association with endometriosis after adjusting for multiple testing; rs758316 in DPP6 on 7q36.2 (P = 0.0045) and rs4837864 in ASTN2 on 9q33.1 (P = 0.0002). Together, the CNV-loci are detected in 6.9% of affected women compared to 2.1% in the general population.

Dataset Information

Pathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays.

Publications

Pathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays.

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