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Expanding the range of ZNF804A variants conferring risk of psychosis.

ABSTRACT: A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).

SUBMITTER: Steinberg S

PROVIDER: S-EPMC3242031 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Expanding the range of ZNF804A variants conferring risk of psychosis.

Steinberg S S Mors O O Børglum A D AD Gustafsson O O Werge T T Mortensen P B PB Andreassen O A OA Sigurdsson E E Thorgeirsson T E TE Böttcher Y Y Olason P P Ophoff R A RA Cichon S S Gudjonsdottir I H IH Pietiläinen O P H OP Nyegaard M M Tuulio-Henriksson A A Ingason A A Hansen T T Athanasiu L L Suvisaari J J Lonnqvist J J Paunio T T Hartmann A A Jürgens G G Nordentoft M M Hougaard D D Norgaard-Pedersen B B Breuer R R Möller H-J HJ Giegling I I Glenthøj B B Rasmussen H B HB Mattheisen M M Bitter I I Réthelyi J M JM Sigmundsson T T Fossdal R R Thorsteinsdottir U U Ruggeri M M Tosato S S Strengman E E Kiemeney L A LA Melle I I Djurovic S S Abramova L L Kaleda V V Walshe M M Walshe M M Bramon E E Vassos E E Li T T Fraser G G Walker N N Toulopoulou T T Yoon J J Freimer N B NB Cantor R M RM Murray R R Kong A A Golimbet V V Jönsson E G EG Terenius L L Agartz I I Petursson H H Nöthen M M MM Rietschel M M Peltonen L L Rujescu D D Collier D A DA Stefansson H H St Clair D D Stefansson K K

Molecular psychiatry 20100105 1

A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-val ...[more]

PMID: 20048749

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Project description:Background. Schizophrenia (SZ) and bipolar disorder (BD) have both been associated with reduced microstructural white matter integrity using, as a proxy, fractional anisotropy (FA) detected using diffusion tensor imaging (DTI). Genetic susceptibility for both illnesses has also been positively correlated in recent genome-wide association studies with allele A (adenine) of single nucleotide polymorphism (SNP) rs1344706 of the ZNF804A gene. However, little is known about how the genomic linkage disequilibrium region tagged by this SNP impacts on the brain to increase risk for psychosis. This study aimed to assess the impact of this risk variant on FA in patients with SZ, in those with BD and in healthy controls. Methods. 230 individuals were genotyped for the rs1344706 SNP and underwent DTI. We used tract-based spatial statistics (TBSS) followed by an analysis of variance, with threshold-free cluster enhancement (TFCE), to assess underlying effects of genotype, diagnosis and their interaction, on FA. Results. As predicted, statistically significant reductions in FA across a widely distributed brain network (p < 0.05, TFCE-corrected) were positively associated both with a diagnosis of SZ or BD and with the double (homozygous) presence of the ZNF804A rs1344706 risk variant (A). The main effect of genotype was medium (d = 0.48 in a 44,054-voxel cluster) and the effect in the SZ group alone was large (d = 1.01 in a 51,260-voxel cluster), with no significant effects in BD or controls, in isolation. No areas under a significant diagnosis by genotype interaction were found. Discussion. We provide the first evidence in a predominantly Caucasian clinical sample, of an association between ZNF804A rs1344706 A-homozygosity and reduced FA, both irrespective of diagnosis and particularly in SZ (in overlapping brain areas). This suggests that the previously observed involvement of this genomic region in psychosis susceptibility, and in impaired functional connectivity, may be conferred through it inducing abnormalities in white matter microstructure.

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Expanding the range of ZNF804A variants conferring risk of psychosis.

Publications

Expanding the range of ZNF804A variants conferring risk of psychosis.

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