Investigation of the ZNF804A gene polymorphism with genetic risk for bipolar disorder in attention deficit hyperactivity disorder

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Abstract

Background

Genome-wide association studies (GWAS) have been conducted on many psychiatric disorders. Evidence from large GWAS indicates that the single nucleotide polymorphism (SNP) rs1344706 in the zinc-finger protein 804A gene ( ZNF804A) is associated with psychotic disorders including bipolar disorder and schizophrenia. One study also found significant association between rs1344706 and the executive control network of attention. In this study we examine the role of the rs1344706 polymorphism that previously showed association with BD and is known to alter expression of the gene in two clinical family-based ADHD samples from the UK and Taiwan.

Findings

To investigate the association between rs1344706 and ADHD, two family samples of ADHD probands from the United Kingdom (n = 180) and Taiwan (n = 212) were genotyped using TaqMan SNP genotyping assays and analysed using within-family transmission disequilibrium test. No significant associations were found between rs1344706 polymorphism and ADHD in either of the samples from Taiwan ( P = 0.91) and UK ( P = 0.41). Even combining the two datasets together the A allele of rs1344706 SNP was still not significantly over-transmitted to affected probands ( P = 0.50). Furthermore, there was no evidence of association with the specific symptoms subgroups of inattention or hyperactivity-impulsivity.

Conclusions

In this study we used family-based ADHD data in the UK and Taiwanese population to test for an association between rs1344706 SNP in the ZNF804A gene and ADHD. Results showed no significant association of rs1344706 with ADHD in UK and Taiwanese samples.

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Most cited references 30

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The Worldwide Prevalence of ADHD: A Systematic Review and Metaregression Analysis

Guilherme Polanczyk (2007)

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Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis

Nigel M. Williams, Irina Zaharieva, Andrew Martin … (2010)

Summary Background Large, rare chromosomal deletions and duplications known as copy number variants (CNVs) have been implicated in neurodevelopmental disorders similar to attention-deficit hyperactivity disorder (ADHD). We aimed to establish whether burden of CNVs was increased in ADHD, and to investigate whether identified CNVs were enriched for loci previously identified in autism and schizophrenia. Methods We undertook a genome-wide analysis of CNVs in 410 children with ADHD and 1156 unrelated ethnically matched controls from the 1958 British Birth Cohort. Children of white UK origin, aged 5–17 years, who met diagnostic criteria for ADHD or hyperkinetic disorder, but not schizophrenia and autism, were recruited from community child psychiatry and paediatric outpatient clinics. Single nucleotide polymorphisms (SNPs) were genotyped in the ADHD and control groups with two arrays; CNV analysis was limited to SNPs common to both arrays and included only samples with high-quality data. CNVs in the ADHD group were validated with comparative genomic hybridisation. We assessed the genome-wide burden of large (>500 kb), rare (<1% population frequency) CNVs according to the average number of CNVs per sample, with significance assessed via permutation. Locus-specific tests of association were undertaken for test regions defined for all identified CNVs and for 20 loci implicated in autism or schizophrenia. Findings were replicated in 825 Icelandic patients with ADHD and 35 243 Icelandic controls. Findings Data for full analyses were available for 366 children with ADHD and 1047 controls. 57 large, rare CNVs were identified in children with ADHD and 78 in controls, showing a significantly increased rate of CNVs in ADHD (0·156 vs 0·075; p=8·9×10−5). This increased rate of CNVs was particularly high in those with intellectual disability (0·424; p=2·0×10−6), although there was also a significant excess in cases with no such disability (0·125, p=0·0077). An excess of chromosome 16p13.11 duplications was noted in the ADHD group (p=0·0008 after correction for multiple testing), a finding that was replicated in the Icelandic sample (p=0·031). CNVs identified in our ADHD cohort were significantly enriched for loci previously reported in both autism (p=0·0095) and schizophrenia (p=0·010). Interpretation Our findings provide genetic evidence of an increased rate of large CNVs in individuals with ADHD and suggest that ADHD is not purely a social construct. Funding Action Research; Baily Thomas Charitable Trust; Wellcome Trust; UK Medical Research Council; European Union.

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Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes

Christopher J. Elia, X Gai, H Xie … (2009)

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable disorder, but specific genetic factors underlying risk remain elusive. To assess the role of structural variation in ADHD, we identified 222 inherited copy number variations (CNVs) within 335 ADHD patients and their parents that were not detected in 2026 unrelated healthy individuals. Although no excess CNVs, either deletions or duplications, were found in the ADHD cohort relative to controls, the inherited rare CNV-associated gene set was significantly enriched for genes reported as candidates in studies of autism, schizophrenia and Tourette syndrome, including A2BP1, AUTS2, CNTNAP2 and IMMP2L. The ADHD CNV gene set was also significantly enriched for genes known to be important for psychological and neurological functions, including learning, behavior, synaptic transmission and central nervous system development. Four independent deletions were located within the protein tyrosine phosphatase gene, PTPRD, recently implicated as a candidate gene for restless legs syndrome, which frequently presents with ADHD. A deletion within the glutamate receptor gene, GRM5, was found in an affected parent and all three affected offspring whose ADHD phenotypes closely resembled those of the GRM5 null mouse. Together, these results suggest that rare inherited structural variations play an important role in ADHD development and indicate a set of putative candidate genes for further study in the etiology of ADHD.

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Journal

Journal ID (nlm-ta): BMC Res Notes

Journal ID (iso-abbrev): BMC Res Notes

Title: BMC Research Notes

Publisher: BioMed Central

ISSN (Electronic): 1756-0500

Publication date Collection: 2013

Publication date (Electronic): 26 January 2013

Volume: 6

Page: 29

Affiliations

[1 ]MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, London, UK

[2 ]School of Medicine, King’s College London, London, UK

[3 ]Department of Psychiatry, Chang Gung Memorial Hospital, Taoyuan, Taiwan

[4 ]Chang Gung University School of Medicine, Taoyuan, Taiwan

[5 ]Division of Mental Health & Drug Abuse Research, National Health Research Institutes, Taoyuan, Taiwan

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Publisher ID: 1756-0500-6-29

DOI: 10.1186/1756-0500-6-29

PMC ID: 3571974

PubMed ID: 23351715

SO-VID: c116f5e8-46a5-4d55-b0c5-5dc7ecba136c

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Investigation of the ZNF804A gene polymorphism with genetic risk for bipolar disorder in attention deficit hyperactivity disorder

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Abstract

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Most cited references 30

The Worldwide Prevalence of ADHD: A Systematic Review and Metaregression Analysis

Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis

Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes

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