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Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder.

ABSTRACT: 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.

SUBMITTER: Elia J

PROVIDER: S-EPMC4310555 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder.

Elia Josephine J Glessner Joseph T JT Wang Kai K Takahashi Nagahide N Shtir Corina J CJ Hadley Dexter D Sleiman Patrick M A PM Zhang Haitao H Kim Cecilia E CE Robison Reid R Lyon Gholson J GJ Flory James H JH Bradfield Jonathan P JP Imielinski Marcin M Hou Cuiping C Frackelton Edward C EC Chiavacci Rosetta M RM Sakurai Takeshi T Rabin Cara C Middleton Frank A FA Thomas Kelly A KA Garris Maria M Mentch Frank F Freitag Christine M CM Steinhausen Hans-Christoph HC Todorov Alexandre A AA Reif Andreas A Rothenberger Aribert A Franke Barbara B Mick Eric O EO Roeyers Herbert H Buitelaar Jan J Lesch Klaus-Peter KP Banaschewski Tobias T Ebstein Richard P RP Mulas Fernando F Oades Robert D RD Sergeant Joseph J Sonuga-Barke Edmund E Renner Tobias J TJ Romanos Marcel M Romanos Jasmin J Warnke Andreas A Walitza Susanne S Meyer Jobst J Pálmason Haukur H Seitz Christiane C Loo Sandra K SK Smalley Susan L SL Biederman Joseph J Kent Lindsey L Asherson Philip P Anney Richard J L RJ Gaynor J William JW Shaw Philip P Devoto Marcella M White Peter S PS Grant Struan F A SF Buxbaum Joseph D JD Rapoport Judith L JL Williams Nigel M NM Nelson Stanley F SF Faraone Stephen V SV Hakonarson Hakon H

Nature genetics 20111204 1

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 rece ...[more]

PMID: 22138692

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Project description:Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ?1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500?kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162?659?756-162?767?019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.

Project description:Attention-deficit/hyperactivity disorder has been identified to involve the impairment of large-scale functional networks within grey matter, and recent studies have suggested that white matter, which also encodes neural activity, can manifest intrinsic functional organization similar to that of grey matter. However, the alterations in white matter functional networks in attention-deficit/hyperactivity disorder remain unknown. We recruited a total of 99 children, including 66 drug-naive patients and 33 typically developing controls aged from 6 to 14, to characterize the alterations in functional networks within white matter in drug-naive children with attention-deficit/hyperactivity disorder. Using clustering analysis, resting-state functional MRI data in the white matter were parsed into different networks. Intrinsic activity within each network and connectivity between networks and the associations between network activity strength and clinical symptoms were assessed. We identified eight distinct white matter functional networks: the default mode network, the somatomotor network, the dorsal attention network, the ventral attention network, the visual network, the deep frontoparietal network, the deep frontal network and the inferior corticospinal-posterior cerebellum network. The default mode, somatomotor, dorsal attention and ventral attention networks showed lower spontaneous neural activity in patients. In particular, the default mode network and the somatomotor network largely showed higher connectivity with other networks, which correlated with more severe hyperactive behaviour, while the dorsal and ventral attention networks mainly had lower connectivity with other networks, which correlated with poor attention performance. In conclusion, there are two distinct patterns of white matter functional networks in children with attention-deficit/hyperactivity disorder, with one being the hyperactivity-related hot networks including default mode network and somatomotor network and the other being inattention-related cold networks including dorsal attention and ventral attention network. These results extended upon our understanding of brain functional networks in attention-deficit/hyperactivity disorder from the perspective of white matter dysfunction.

Dataset Information

Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder.

Publications

Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder.

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