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Further evidence for association between ErbB4 and schizophrenia and influence on cognitive intermediate phenotypes in healthy controls

Molecular Psychiatry volume 11, pages 1062–1065 (2006)Cite this article

An Erratum to this article was published on 27 August 2007

Two recent reports have shown evidence for association between single-nucleotide polymorphisms (SNPs) in ErbB4 and schizophrenia.1, 2 In addition, one found support for statistical interaction between NRG1 and ErbB4 resulting in increased risk of schizophrenia,1 although evidence for statistical interaction was only observed in ErbB4 heterozygotes, which is difficult to interpret. Knockout NRG1/ErbB4 mice exhibit behavioral abnormalities thought to coincide with selected aspects of schizophrenia in humans.3 Based on these intriguing statistical and biobehavioral findings, we sought to assess association between ErbB4 and schizophrenia status in three independent family-based samples. In addition, we examined whether ErbB4 was associated with cognitive test scores in healthy controls that have been shown to be related to increased genetic risk for schizophrenia.4, 5 A thorough examination of epistasis between ErbB4, NRG1, and other protein complex-binding partners is currently underway,6 and will be reported in the future.

A family-based sample (N=296 families) was ascertained as part of the Clinical Brain Disorders Branch/National Institute of Mental Health Sibling Study (SS), the details of which are described elsewhere.7 All subjects were diagnosed using the Structured Clinical Interview (SCID). Probands met Diagnostic and Statistical Manual-IV (DSM-IV) criteria for broad schizophrenia diagnosis. Control individuals (N=370) were ascertained from the National Institutes of Health Normal Volunteer Office and were screened by SCID diagnosis for psychiatric disorders, again as described previously.7 All participants gave informed consent and self-identified as Caucasian. Two additional independent family-based samples (Caucasian (N=71 families), African American (N=51 families)) were ascertained through the NIMH Genetics Initiative (NIMHGI). Genotypes for all SNPs were obtained using the Taqman 5′-exonuclease allelic discrimination assay. Hardy–Weinberg Equilibrium (HWE) was tested using exact tests. Analyses of single SNPs were conducted using Family Based Association Test (FBAT) in nuclear families8 and linear regression in the healthy controls using STATA, version 8.2 (College Park, TX, USA). Haplotype analysis was performed using FBAT for families and the R package haplo.stats9 in healthy controls. P-values have not been adjusted for multiple testing in any sample. Cognitive intermediate phenotypes were tested in control subjects and were based on seven normalized derived factor scores. In a factor analysis of 24 variables from nine neuropsychological tests shown to be associated with increased genetic risk for schizophrenia,4, 5, 10 seven factors were identified that explained 68% of the variance on these measures (Genderson M, Aper-Diaz CM, Weinberger DR, Goldberg TE, unpublished data). These factors were labeled: visual memory (comprised of specific subscales of the (Weschler memory scale and the California Verbal Learning Test (CVLT)), working memory (N back test), verbal memory (story recall), processing speed Wechsler Adult Intelligence Scale (WAIS), Trail Making Test (TRAILS), Fluency), executive function (Wisconsin Card Sorting Test (WCST)), attention (Continuous Performance Test (CPT) and digit span). SNPs were selected to replicate prior reports, so previously positively associated SNPs and several related tag SNPs selected from HapMap (www.hapmap.org)1, 2 were chosen for genotyping. Several previously reported SNPs were not available with our assay.

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References

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  6. Nicodemus KK, Kolachana BS, Mathew S, Vakkalanka R, Hyde T, Straub RE et al. The 11th International Congress of Human Genetics, Brisbane, Australia, 4–10 August, 2006; http://www.ichg2006.com/abstract/975.htm.

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Authors and Affiliations

  1. Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    K K Nicodemus, A Luna, R Vakkalanka, T Goldberg, M Egan, R E Straub & D R Weinberger

  2. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    K K Nicodemus

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  1. K K Nicodemus
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  2. A Luna
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  3. R Vakkalanka
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  7. D R Weinberger
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Correspondence to D R Weinberger.

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Nicodemus, K., Luna, A., Vakkalanka, R. et al. Further evidence for association between ErbB4 and schizophrenia and influence on cognitive intermediate phenotypes in healthy controls. Mol Psychiatry 11, 1062–1065 (2006). https://doi.org/10.1038/sj.mp.4001878

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