Evidence for the involvement of ZNF804A in cognitive processes of relevance to reading and spelling

Abstract

Previous studies have shown that individuals with schizophrenia and dyslexia display common neurocognitive abnormalities. The aim of the present study was to determine whether known schizophrenia-risk genes contribute to dyslexia risk or to disease-relevant cognitive functions. For this purpose, we genotyped the schizophrenia-associated risk variants within zinc-finger protein 804A (ZNF804A), transcription-factor 4 and neurogranin in a large dyslexia case-control sample. We tested all variants for association with dyslexia (927 cases, 1096 controls), and with eight language-relevant cognitive processes (1552 individuals). We observed six significant associations between language-relevant traits and the ZNF804A-variant rs1344706. Interestingly, the ZNF804A schizophrenia risk variant was associated with a better cognitive performance in our data set. This finding might be consistent with a previously reported ZNF804A association in schizophrenia, in which patients carrying the schizophrenia-risk allele at rs1344706 showed a better performance in two memory tests. In conclusion, the present study provides evidence that ZNF804A might have a role in cognitive traits of relevance to reading and spelling, and underlines the phenotypic complexity that might be associated with ZNF804A.

Citation: Transl Psychiatry (2012) 2, e136, doi:10.1038/tp.2012.62

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Evidence for the involvement of ZNF804A in cognitive processes of relevance to reading and spelling

J Becker1,2, D Czamara3, P Hoffmann1,2, K Landerl4, L Blomert5, D Brandeis6,7,8, A Vaessen5, U Maurer6,9, K Moll10,12, KU Ludwig1,2, B Mller-Myhsok3, MM Nthen1,2, G Schulte-Krne11 and J Schumacher1

Previous studies have shown that individuals with schizophrenia and dyslexia display common neurocognitive abnormalities. The aim of the present study was to determine whether known schizophrenia-risk genes contribute to dyslexia risk or to disease-relevant cognitive functions. For this purpose, we genotyped the schizophrenia-associated risk variants within zinc-nger protein 804A (ZNF804A), transcription-factor 4 and neurogranin in a large dyslexia casecontrol sample. We tested all variants for association with dyslexia (927 cases, 1096 controls), and with eight language-relevant cognitive processes (1552 individuals). We observed six signicant associations between language-relevant traits and the ZNF804A-variant rs1344706. Interestingly, the ZNF804A schizophrenia risk variant was associated with a better cognitive performance in our data set. This nding might be consistent with a previously reported ZNF804A association in schizophrenia, in which patients carrying the schizophrenia-risk allele at rs1344706 showed a better performance in two memory tests. In conclusion, the present study provides evidence that ZNF804A might have a role in cognitive traits of relevance to reading and spelling, and underlines the phenotypic complexity that might be associated with ZNF804A.

Translational Psychiatry (2012) 2, e136; doi:http://dx.doi.org/10.1038/tp.2012.62

Web End =10.1038/tp.2012.62 ; published online 10 July 2012

Introduction

Several genome-wide association studies have been performed for schizophrenia to date, and zinc-nger protein 804A (ZNF804A), transcription-factor 4 (TCF4) and neurogranin (NRGN) were among the rst genes to achieve genome-wide signicance.1,2 These ndings have since been replicated in independent samples, and these genes are therefore likely to represent true risk factors for schizophrenia.3

Given that individuals with dyslexia and schizophrenia have been reported to display certain common neurocognitive abnormalities,4,5 we were interested in determining whether these genes contribute to dyslexia risk or to disease-relevant cognitive functions. For this purpose, we genotyped the identied schizophrenia risk variants in ZNF804A (rs1344706), TCF4 (rs9960767) and NRGN (rs12807809) in ve dyslexia casecontrol samples of Central European descent. Subsequently, we performed association analyses using casecontrol status (927 cases and 1096 controls) and eight dyslexia-relevant psychometric tests (1552 individuals). The psychometric tests encompass the dyslexia core symptoms of impaired reading and spelling (word reading, word spelling), phonological awareness (phoneme deletion), phonological coding (non-word reading), auditory short-term

memory (digit span) and rapid naming (letters, digits, pictures).

Materials and methods

We investigated ve dyslexia casecontrol samples from Salzburg (Austria), Zurich (Switzerland), Marburg (Germany), Munich (Germany) and Maastricht (The Netherlands). The whole sample set was comprised of 927 dyslexia cases and 1096 controls. Besides casecontrol status, data on eight language-relevant cognitive processes were available for all individuals, with the exception of the Marburg-controls (N 1552, Supplementary Table 1). These eight cognitive

processes include word reading, word spelling, phonological awareness (phoneme deletion), phonological coding (non-word reading), auditory short-term memory (digit span) and rapid naming (letters, digits, pictures). Details of the phenotypic measures are provided in Supplementary Table 2.

Genotyping of the variants of interest was carried out on the Sequenom MassArray system (Sequenom, San Diego, CA, USA). Primer sequences and standard assay conditions are available upon request.

1Institute of Human Genetics, University of Bonn, Bonn, Germany; 2Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany; 3Max Planck Institute of Psychiatry, Munich, Germany; 4Department of Psychology, University of Graz, Graz, Austria; 5Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience, Maastricht Brain Imaging Institute (M-BIC), Maastricht University, Maastricht, The Netherlands; 6Department of Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland; 7Zurich Center for Integrative Human Physiology (ZIHP), Zurich, Switzerland; 8Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany; 9Department of Psychology, University of Zurich, Zurich, Switzerland; 10Department of Psychology, University of Salzburg, Salzburg, Austria and 11Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital Munich, Munich, GermanyCorrespondence: Dr Johannes Schumacher, Institute of Human Genetics, University of Bonn, Sigmund-Freud-Strasse 25, D-53105 Bonn, Germany.

E-mail: [email protected]

12Current address: Department of Psychology, University of York, York, UK.

Keywords: cognitive processes; dyslexia; genetic association; reading and spelling; schizophrenia; ZNF804A

Received 27 Feburary 2012; revised 15 May 2012; accepted 31 May 2012

ZNF804A association with reading and spelling

J Becker et al

2

Association analyses were performed using PLINK.6 Logistic regression was used for casecontrol analyses, and linear regression was used for quantitative trait analyses. To avoid false-positive results due to possible population stratication in our sample set, we performed an inverse variance weighted xed effects meta-analysis using the R-library rmeta (http://www.r-project.org/

Web End =http://www.r-project.org/).

Results

In 927 dyslexia cases and 1096 controls, no dyslexia association was found for TCF4 or NRGN (Supplementary Tables 3 and 4). Although the association between rs1344706 in ZNF804A and dyslexia was not statistically signicant, we observed a similar genetic effect size (odds ratio 1.12,

Table 1) as that reported previously in patients with schizophrenia (odds ratio 1.09).1 Notably, the ZNF804A schizo

phrenia-protective allele was more common in dyslexia patients.

In a second step, we combined all cases and controls (1552 individuals) and tested whether the schizophrenia-risk genes were involved in language-relevant cognitive processes. Negative results were obtained for the variants in TCF4 and NRGN (Supplementary Tables 3 and 4). In contrast, rs1344706 in ZNF804A showed association with six pheno-types (Table 1). Here, the schizophrenia-protective allele and the schizophrenia-risk allele were consistently associated with a poorer and a better performance in all cognitive tests, respectively. After correction for multiple testing, the associations with word reading, non-word reading and rapid naming of digits remained signicant. Forest plots of rs1344706 for the casecontrol analysis and eight quantitative trait analyses are provided in Supplementary Figure 1. Furthermore, we performed a heterogeneity analysis and observed no differences between the rs1344706 effect sizes for the ve subsamples: Salzburg, Zurich, Marburg, Munich and Maastricht (P40.05, Supplementary Table 5). The estimated effect sizes for the association between rs1344706 and the cognitive phenotypes are shown in Supplementary Table 6. Finally, we tested whether rs1344706 was associated with the intelligence quotient level, and observed no association (Supplementary Table 7).

Discussion

The present ndings provide evidence that ZNF804A might be involved in cognitive functions of relevance to reading and spelling. This hypothesis might be supported by the 2q31.2-2q32.3-deletion syndrome phenotype, which includes severe speech impairment.7 ZNF804A is one of the few genes present within the deleted region, and previous authors have speculated that the deletion in ZNF804A may inuence the speech phenotype in 2q31.2-2q32.3-syndrome patients.7 Furthermore, our data provide evidence that the allele at ZNF804A-rs1344706 that inuences the risk for schizophrenia might be associated with a better performance in language-relevant processes. In contrast, the schizophrenia-protective allele at rs1344706 appeared to be associated with a poorer performance in cognitive processes of relevance to reading and spelling. A similar effect was observed in a

Table1Dyslexiacasecontrolassociationanalysis(above)andquantitativetraitanalysisincasesandcontrols(below)usingrs1344706inZNF804A

Maastricht,

141cases/169controls

CasecontrolanalysisAlleleb ORP-valueORP-valueORP-valueORP-valueORP-valueORP-value

G1.120.08431.360.03890.620.22441.000.99921.260.12301.180.3349

0.15850.04790.11100.6589 0.10100.1500 0.22110.0234 0.16720.2428

WordspellingG 0.10400.0196 0.06420.46830.14060.6595 0.06810.3316 0.28740.0047 0.05640.6515

DigitspanG 0.03140.40030.02280.77020.16610.4384 0.03200.6475 0.06320.3748 0.08440.3381

Non-wordreadingG 0.16730.0005

0.10630.18840.03120.8721 0.15580.0257 0.21230.0221 0.11760.3185

RN:picturesG 0.05270.1991 0.07460.3550 0.10280.6412 0.08950.2017 0.12360.17380.16690.1073

PhonemedeletionG 0.09420.0263 0.17690.0325 0.40510.04620.04670.5059 0.14440.1281 0.13870.2501

Abbreviations:OR,oddsratio;RN,rapidnaming.

a P-valuesforthecombinedsamplewerecalculatedonthebasisofaxedeffectsmeta-analysis.b Referenceallele,wherebyGrepresentstheprotectivealleleintheschizophreniaassociationstudyperformedby

ODonovanetal.1 c Afteracorrectionbyafactorof27(3variants 9tests),theassociationsforwordreading(P0.0297),non-wordreading(P0.0135)andrapidnamingofdigits(P0.0189)remainedsignicant.

Theresultsfortheanalysisofeachofthevesubsamplesandanalysesacrossallsubsamplesareshown.NominalP-valueso0.05aredepictedinbold.brepresentstheregressioncoefcient.

Maastricht,

310individuals

QuantitativetraitanalysisAlleleb bP-valuebP-valuebP-valuebP-valuebP-valuebP-value

Munich,

171cases/210controls

Munich,

381individuals

Marburg,

400cases/471controls

Marburg,

400individuals

0.17240.11970.10680.7012 0.14410.0396 0.32100.0044 0.09110.4933

RN:lettersG 0.11940.0048 0.05660.5033 0.13480.5094 0.17520.0123 0.20790.02910.04980.6643

RN:digitsG 0.14060.0007

Zurich,

30cases/43controls

Zurich,

73individuals

Salzburg,

185cases/203controls

Salzburg,

388individuals

927cases/1096controlsa

c

c

c

TestsAll,

WordreadingG 0.14160.0011

All,

1552individualsa

Translational Psychiatry

ZNF804A association with reading and spelling J Becker et al

3

previous study, which analyzed cognitive prole in two schizophrenia samples.8 In that study, patients carrying the ZNF804A schizophrenia-risk allele also showed a signicantly better performance in two memory tests compared with patients carrying the protective allele. However, it is difcult to assess the extent to which these two studies and their ndings can be compared, as different cognitive tests were applied. Another interesting aspect of the present study is that impairments in ZNF804A-associated cognitive functions (word reading, word spelling, non-word reading, rapid naming: letters and digits, and phoneme deletion) constitute the characteristic pattern of dyslexia.9 Therefore, additional studies of larger samples are required to determine the precise role of ZNF804A in dyslexia per se.

In summary, the same rs1344706 allele in ZNF804A was associated with a better performance in language-related cognitive functions in the present cohort, and was associated with schizophrenia in previous independent studies. If our ndings are true, it remains unknown whether these two phenotypes are mediated by the same or different neuro-biological pathways, and whether previously reported ZNF804A-imaging ndings in healthy individuals10 reect schizophrenia- and/or language-related cognitive processes.

The present ndings underline the phenotypic complexity that might be associated with ZNF804A, and illustrate the benet of testing neurocognitive phenotypes in studies of dyslexia.

Conict of interest

The authors declare no conict of interest.

Acknowledgements. This work was funded by the EU FP6 Program NeuroDys, the Austrian Science Fund (Project 18351-B02) and the Swiss National Science Foundation (Project 32-108130).

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