Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder

Williams, Hywel; Norton, Nadine; Dwyer, Sarah; Moskvina, Valentina; Nikolov, Ivan; Carroll, Liam; Georgieva, Lyudmila; Williams, Nigel; Morris, Derek W.; Quinn, Emma M.; Giegling, Ina; Ikeda, Masashi; Wood, Joel; Lencz, Todd; Hultman, Christina M.; Lichtenstein, Paul; Thiselton, Dawn L.; Maher, Brion S.; Malhotra, Anil K.; Riley, Brien P.; Kendler, Kenneth S.; Gill, Michael; Sullivan, Patrick F.; Sklar, Pamela; Purcell, Shaun; Nimgaonkar, Vishwajit L.; Kirov, George; Holmans, Peter Alan; Corvin, Aiden; Rujescu, Dan; Craddock, Nick; Owen, Michael John; O'Donovan, Michael Conlon

doi:10.1038/mp.2010.36

Cited by 261 publications

(222 citation statements)

References 31 publications

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“…Consistent with previous studies (Riley et al, 2010;Williams et al, 2011;Steinberg et al, 2011;Zhang et al, 2011;Xiao et al, 2011, see Li et al, 2011, for an exception), the current study found evidence for the association between rs1344706 and schizophrenia. In addition, we replicated results of Walters et al (2010) that the association between rs1344706 and schizophrenia became stronger when the samples were limited to those with relatively high IQ.…”

Section: Discussionsupporting

confidence: 92%

“…Recently, an intronic SNP in this gene, rs1344706, has been found to be one of the most compelling candidate SNPs for schizophrenia. As shown by a recent whole genome study (O'Donovan et al, 2008) and several follow-up replications (Riley et al, 2010;Williams et al, 2011;Steinberg et al, 2011), there is a strong association between this SNP and schizophrenia with the A allele being the risk allele. This association has also been replicated among Han Chinese population in two studies Xiao et al, 2011) but not a third one .…”

Section: Introductionmentioning

confidence: 89%

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Evidence of IQ-Modulated Association Between ZNF804A Gene Polymorphism and Cognitive Function in Schizophrenia Patients

Chen

Zhai

et al. 2012

Neuropsychopharmacol

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ZNF804A gene polymorphism rs1344706 has been suggested as the most compelling case of a candidate gene for schizophrenia by a genome-wide association study and several replication studies. The current study of 570 schizophrenia patients and 448 controls again found significantly different genotype frequencies of rs1344706 between patients and controls. More important, we found that this association was modulated by IQ, with a stronger association among individuals with relatively high IQ, which replicated results of Walters et al, 2010. We further examined whether this IQ-modulated association also existed between the SNP and the intermediate phenotypes (working memory and executive functions) of schizophrenia. Data were available from an N-back task (366 patients and 414 controls) and the attention network task (361 patients and 416 controls). We found that the SNP and IQ had significant interaction effects on the intermediate phenotypes for patients, but not for controls. The disease risk allele was associated with poorer cognitive function in patients with high IQ, but better cognitive function in patients with low IQ. Together, these results indicated that IQ may modulate the role of rs1344706 in the etiology of both schizophrenia and its cognitive impairments, and pointed to the necessity of considering general cognitive function as indexed by IQ in the future studies of genetic bases of schizophrenia.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 89%

Evidence of IQ-Modulated Association Between ZNF804A Gene Polymorphism and Cognitive Function in Schizophrenia Patients

Chen

Zhai

et al. 2012

Neuropsychopharmacol

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“…For this, it is necessary to compare cDNA allele ratios in heterozygotes for the risk variant (where any cis ‐regulatory effects of the two alleles will differ) with those in homozygotes for the risk variant (where any cis ‐regulatory effects of the variant will be equal) [Bray et al, 2003a, 2005; Williams et al, 2011; Hill and Bray, 2012]. Small genotype groups precluded such an assessment of cis ‐regulatory effects of rs11191419, but genotype at ch10_104957618_I was associated with significant effects on the allelic expression of BORCS7 in fetal brain, adult DLPFC, adult hippocampus and adult caudate, AS3MT in the fetal brain and adult caudate, and NT5C2 in the fetal brain, adult DLPFC and adult hippocampus.…”

Section: Resultsmentioning

confidence: 99%

Genome‐wide significant schizophrenia risk variation on chromosome 10q24 is associated with altered cis‐regulation of BORCS7, AS3MT, and NT5C2 in the human brain

Duarte

Troakes

Nolan

et al. 2016

American J of Med Genetics Pt B

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Chromosome 10q24.32‐q24.33 is one of the most robustly supported risk loci to emerge from genome‐wide association studies (GWAS) of schizophrenia. However, extensive linkage disequilibrium makes it difficult to distinguish the actual susceptibility gene(s) at the locus, limiting its value for improving biological understanding of the condition. In the absence of coding changes that can account for the association, risk is likely conferred by altered regulation of one or more genes in the region. We, therefore, used highly sensitive measures of allele‐specific expression to assess cis‐regulatory effects associated with the two best‐supported schizophrenia risk variants (SNP rs11191419 and indel ch10_104957618_I/rs202213518) on the primary positional candidates BORCS7, AS3MT, CNNM2, and NT5C2 in the human brain. Heterozygosity at rs11191419 was associated with increased allelic expression of BORCS7 and AS3MT in the fetal and adult brain, and with reduced allelic expression of NT5C2 in the adult brain. Heterozygosity at ch10_104957618_I was associated with reduced allelic expression of NT5C2 in both the fetal and adult brain. Comparisons between cDNA ratios in heterozygotes and homozygotes for the risk alleles indicated that cis‐effects on NT5C2 expression in the adult dorsolateral prefrontal cortex could be largely accounted for by genotype at these two risk variants. While not excluding effects on other genes in the region, this study implicates altered neural expression of BORCS7, AS3MT, and NT5C2 in susceptibility to schizophrenia arising from genetic variation at the chromosome 10q24 locus. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

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“…It is also possible that other white matter tracts, not examined in this study, might have been influenced by this risk variant. In addition, although there is evidence to support the rs1344706 SNP as the actual risk variant within the ZNF804A gene (Riley et al, 2010;Williams et al, 2010), it is possible that a nearby SNP in linkage disequilibrium with rs1344706 may be the causative risk variant. Regarding cognitive performance, although a significant genotype by cognitive task interaction was found, our follow-up analysis demonstrating the effect of genotype on attention control would not have survived Bonferroni's correction.…”

Section: Discussionmentioning

confidence: 99%

The ZNF804A Gene: Characterization of a Novel Neural Risk Mechanism for the Major Psychoses

Voineskos

Lerch

Felsky

et al. 2011

Neuropsychopharmacol

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Schizophrenia and bipolar disorder share genetic risk, brain vulnerability, and clinical symptoms. The ZNF804A risk variant, rs1344706, confers susceptibility for both disorders. This study aimed to identify neural mechanisms common to both schizophrenia and bipolar disorder through this variant's potential effects on cortical thickness, white matter tract integrity, and cognitive function. Imaging, genetics, and cognitive measures were ascertained in 62 healthy adults aged between 18 and 59 years. High-resolution multimodal MRI/DTI imaging was used to measure cortical thickness and major frontotemporal and interhemispheric white matter tracts. The general linear model was used to examine the influence of the ZNF804A rs1344706 risk variant on cortical thickness, white matter tract integrity, and cognitive measures. Individuals homozygous for the risk variant ('A' allele) demonstrated reduced cortical gray matter thickness in the superior temporal gyrus, and in the anterior and posterior cingulate cortices compared with C-allele carriers. No effect of the risk variant on microstructural integrity of white matter tracts was found. Reduced attention control was found in risk allele homozygotes, aligning with findings in the anterior cingulate cortex. Our data provide a novel, genetically based neural risk mechanism for the major psychoses by effects of the ZNF804A risk variant on neural structures and cognitive function susceptible in both disorders. Our findings link genetic, imaging, and cognitive susceptibility relevant to both schizophrenia and bipolar disorder.

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Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder

Cited by 261 publications

References 31 publications

Evidence of IQ-Modulated Association Between ZNF804A Gene Polymorphism and Cognitive Function in Schizophrenia Patients

Evidence of IQ-Modulated Association Between ZNF804A Gene Polymorphism and Cognitive Function in Schizophrenia Patients

Genome‐wide significant schizophrenia risk variation on chromosome 10q24 is associated with altered cis‐regulation of BORCS7, AS3MT, and NT5C2 in the human brain

The ZNF804A Gene: Characterization of a Novel Neural Risk Mechanism for the Major Psychoses

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