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

Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Nature Genetics (Impact Factor: 29.35). 12/2011; 44(1):78-84. DOI: 10.1038/ng.1013
Source: PubMed

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.

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Available from: Gholson J Lyon, Sep 25, 2015
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    • "The evidence for this model is strong and also supported by numerous studies documenting an increased incidence of ADHD symptoms and ADHDrelated cognitive vulnerabilities in family members of ADHD probands (Rommelse et al. 2011; Rommelse 2008). However, several recent reports do indicate that rare genetic mutations or non-shared environmental factors (such as low birth weight and medical conditions) with a large effect may relate to ADHD as well (Lionel et al. 2011; Williams et al. 2010, 2012; Elia et al. 2012; Ben Amor et al. 2005). These findings suggest that applying the SPX–MPX stratification in ADHD families may also be worthwhile. "
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    ABSTRACT: Autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) are highly heterogeneous neuropsychiatric disorders, that frequently co-occur. This study examined whether stratification into single-incidence (SPX) and multi-incidence (MPX) is helpful in (a) parsing heterogeneity and (b) detecting overlapping and unique underpinnings of the disorders. ASD and ADHD traits were measured in 56 ASD/31 ADHD SPX families, 59 ASD/171 ADHD MPX families and 203 control families. In ASD but not ADHD, behavioral traits were less elevated in SPX than MPX unaffected relatives, suggesting that SPX-MPX stratification may thus help parse ASD, but not ADHD heterogeneity. Particularly unaffected relatives from MPX ASD/ADHD families displayed elevated trait levels of both disorders, indicating shared (multifactorial) underpinnings underlying ASD and ADHD in these families. Cross-disorder traits were highest in MPX ASD unaffected siblings.
    Journal of Autism and Developmental Disorders 08/2014; 45(3). DOI:10.1007/s10803-014-2220-9 · 3.34 Impact Factor
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    • "Deletions and duplications in GRM7 were found in the UCL1 bipolar sample as well [McQuillin et al., 2011]. Rare CNVs occurring within GRM7 have been documented in patients with other psychiatric disorder patients, such as mood disorder [Saus et al., 2010], schizophrenia [Walsh et al., 2008] and ADHD [Elia et al., 2012]. A growing body of evidence suggests a strong relationship between mGluR7 function and the action of antidepressants and mood-stabilizers [Palucha, 2006]. "
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    ABSTRACT: Genetic markers at the GRM7 gene have shown allelic association with bipolar disorder (BP) in several case–control samples including our own sample. In this report, we present results of resequencing the GRM7 gene in 32 bipolar samples and 32 random controls selected from 553 bipolar cases and 547 control samples (UCL1). Novel and potential etiological base pair changes discovered by resequencing were genotyped in the entire UCL case–control sample. We also report on the association between GRM7 and BP in a second sample of 593 patients and 642 controls (UCL2). The three most significantly associated SNPs in the original UCL1 BP GWAS sample were genotyped in the UCL2 sample, of which none were associated. After combining the genotype data for the two samples only two (rs1508724 and rs6769814) of the original three SNP markers remained significantly associated with BP. DNA sequencing revealed mutations in three cases which were absent in control subjects. A 3′-UTR SNP rs56173829 was found to be significantly associated with BP in the whole UCL sample (P = 0.035; OR = 0.482), the rare allele being less common in cases compared to controls. Bioinformatic analyses predicted a change in the centroid secondary structure of RNA and alterations in the miRNA binding sites for the mutated base of rs56173829. We also validated two deletions and a duplication within GRM7 using quantitative-PCR which provides further support for the pre-existing evidence that copy number variants at GRM7 may have a role in the etiology of BP. © 2014 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Published by Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2014; 165(4). DOI:10.1002/ajmg.b.32239 · 3.42 Impact Factor
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    • "Screening upstream targets of FMR1, the same group identified a deletion in GRM5 that removes a single amino acid, causing an additional substitution at the same site. GRM5 encodes the glutamate receptor mGluR5 (Bear et al., 2004), which has been proposed as translational target in both ASD and ADHD (Elia et al., 2012; Silverman et al., 2012). "
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    ABSTRACT: The goal of this paper is to review recent research on copy number variations (CNVs) and their association with complex and rare diseases. In the latter part of this paper, we focus on how large biorepositories such as the electronic medical record and genomics (eMERGE) consortium may be best leveraged to systematically mine for potentially pathogenic CNVs, and we end with a discussion of how such variants might be reported back for inclusion in electronic medical records as part of medical history.
    Frontiers in Genetics 03/2014; 5:51. DOI:10.3389/fgene.2014.00051
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