Genome-wide study identifies PTPRO and WDR72 and FOXQ1-SUMO1P1 interaction associated with neurocognitive function

Abstract

Background

Several aspects of neurocognitive function have high heritability, but the molecular genetic mechanisms underlying neurocognition are not known. We performed a genome-wide association study (GWAS) to identify genes associated with neurocognition.

Methods

700 Subjects (schizophrenia spectrum disorder, n = 190, bipolar disorder n = 157 and healthy individuals n = 353) were tested with an extensive neuropsychological test battery, and genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0. After quality control, linear regression analysis of each of the 24 cognitive tests on the SNP dosage was performed, including age, gender, education and disease group as covariates. Additionally, 9 SNPs trending toward genome-wide significance were considered for epistatic interactions.

Results

Four SNPs and 2 independent association signals achieving genome-wide significance were identified. Three intronic SNPs in PTPRO were associated with learning and memory (CVLT-II LDFR) (rs17222089, p = 1.55 × 10⁻⁸; rs11056571, p = 1.68 × 10⁻⁸; and rs2300290, p = 1.09 × 10⁻⁸). rs719714 downstream of WDR72 was associated with executive functioning (CW-3: Inhibition, D-KEFS) (p = 4.32 × 10⁻⁸). A highly significant epistatic interaction was found between rs9378605 upstream of FOXQ1 and rs11699311 downstream of SUMO1P1 for the Grooved Pegboard test (p = 7.6 × 10⁻¹⁴).

Conclusions

We identified four novel loci associated with neurocognitive function and one novel epistatic interaction. The findings should be replicated in independent samples, but indicate a role of PTPRO in learning and memory, WDR72 with executive functioning, and an interaction between FOXQ1 and SUMO1P1 for psychomotor speed.

Introduction

Neurocognitive function is essential for most daily life activities, and seems to play a role in evolution of humans (Balter, 2010). Neurocognitive dysfunction is seen in a range of brain disorders, from neurodevelopmental to neurodegenerative disorders (Bora et al., 2009, Lott and Dierssen, 2010, Geschwind, 2009). Cognitive impairment, particularly in learning and memory and executive functioning, has been associated with severe mental disorders, especially schizophrenia but also bipolar disorders (Simonsen et al., 2009, Bora et al., 2009).

Several lines of evidence indicate that neurocognitive functions are heritable (McClearn et al., 1997, Finkel et al., 1995, Bouchard et al., 1990). A new study has estimated the heritability of intelligence to ∼40–51% (Davies et al., 2011), and for other neurocognitive domains there are indications of same range of heritability (Green et al., 2008). Despite the clear evidence for genetic factors, the molecular mechanisms underlying cognitive functions are not well understood.

Investigations of candidate genes implicate the involvement of COMT, BDNF and genes related to severe mental disorders in cognitive function (Egan et al., 2001, Egan et al., 2003, Porteous et al., 2006). Animal studies have suggested genetic effects on learning and memory (Arguello and Gogos, 2010, Crawley, 2008). Recent evidence has indicated overlapping genetic mechanisms in severe mental disorders and cognitive functioning (Burdick et al., 2010, Toulopoulou et al., 2007). Given this emerging but incomplete picture of the relationship between genetics, disease and neurocognition, it is reasonable to further investigate the genetic effects on neurocognition in clinical samples, particularly using a hypothesis-free genome-wide study approach. This approach has proven useful for identification of genetic factors of cognition (Papassotiropoulos et al., 2006, Butcher et al., 2008, Bates et al., 2009) although the findings do not always replicate (Need et al., 2008).

Recent evidence suggests possible epistatic interactions between susceptibility genes for neuropsychiatric disorders. An fMRI study found an epistatic interaction between COMT and GRM3 on the engagement of the prefrontal cortex during working memory (Tan et al., 2007). DISC1, CIT and NDEL1 have also been implicated in epistatic interactions for both susceptibility to schizophrenia and prefrontal cortex inefficiency (Nicodemus et al., 2010). Thus, investigation of epistatic interactions of genes associated with neurocognitive domains is sensible.

The aim of the current study was to identify genetic variants associated with tests in neurocognitive domains. We used genome-wide genotyping technology together with an extensive neuropsychological test battery in a genetically homogenous sample of healthy individuals and psychiatric patients.