Genome-wide study identifies PTPRO and WDR72 and FOXQ1-SUMO1P1 interaction associated with neurocognitive function.
ABSTRACT 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.
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.
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)).
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.
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ABSTRACT: We propose a new approach to detect gene × gene joint action in genome-wide association studies (GWASs) for case-control designs. This approach offers an exhaustive search for all two-way joint action (including, as a special case, single gene action) that is computationally feasible at the genome-wide level and has reasonable statistical power under most genetic models. We found that the presence of any gene × gene joint action may imply differences in three types of genetic components: the minor allele frequencies and the amounts of Hardy-Weinberg disequilibrium may differ between cases and controls, and between the two genetic loci the degree of linkage disequilibrium may differ between cases and controls. Using Fisher's method, it is possible to combine the different sources of genetic information in an overall test for detecting gene × gene joint action. The proposed statistical analysis is efficient and its simplicity makes it applicable to GWASs. In the current study, we applied the proposed approach to a GWAS on schizophrenia and found several potential gene × gene interactions. Our application illustrates the practical advantage of the proposed method.Genetic Epidemiology 01/2014; 38(1). · 4.02 Impact Factor
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ABSTRACT: RNA-sequencing (RNA-seq) is a powerful technique to investigate the complexity of gene expression in the human brain. We used RNA-seq to survey the brain transcriptome in high-quality postmortem dorsolateral prefrontal cortex from 11 individuals diagnosed with bipolar disorder (BD) and from 11 age- and gender-matched controls. Deep sequencing was performed, with over 350 million reads per specimen. At a false discovery rate of <5%, we detected five differentially expressed (DE) genes and 12 DE transcripts, most of which have not been previously implicated in BD. Among these, Prominin 1/CD133 and ATP-binding cassette-sub-family G-member2 (ABCG2) have important roles in neuroplasticity. We also show for the first time differential expression of long noncoding RNAs (lncRNAs) in BD. DE transcripts include those of serine/arginine-rich splicing factor 5 (SRSF5) and regulatory factor X4 (RFX4), which along with lncRNAs have a role in mammalian circadian rhythms. The DE genes were significantly enriched for several Gene Ontology categories. Of these, genes involved with GTPase binding were also enriched for BD-associated SNPs from previous genome-wide association studies, suggesting that differential expression of these genes is not simply a consequence of BD or its treatment. Many of these findings were replicated by microarray in an independent sample of 60 cases and controls. These results highlight common pathways for inherited and non-inherited influences on disease risk that may constitute good targets for novel therapies.Molecular Psychiatry advance online publication, 7 January 2014; doi:10.1038/mp.2013.170.Molecular psychiatry 01/2014; · 15.05 Impact Factor
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ABSTRACT: Cognitive decline is a reduction in cognitive ability usually associated with aging, and those with more extreme cognitive decline either have or are at risk of progressing to mild cognitive impairment and dementia including Alzheimer's disease (AD). We hypothesized that genetic variants predisposing to AD should be predictive of cognitive decline in elderly individuals. We selected 1325 subjects with extreme cognitive decline and 1083 well-matched control subjects from the Guangzhou Biobank Cohort Study in which more than 30,000 southern Chinese older people have been recruited and followed up. Thirty single-nucleotide polymorphisms in 29 AD-associated genes were genotyped. No statistically significant allelic associations with cognitive decline were found by individual variant analysis. At the level of genotypic association, we confirmed that the APOE ε4 homozygote significantly accelerated cognitive decline and found that carriers of the ACE rs1800764_C allele were more likely to show cognitive decline than noncarriers, particularly in those without college education. However, these effects do not survive after multiple testing corrections, and together they only explain 1.7% of the phenotypic variance in cognitive score change. This study suggests that AD risk variants and/or genes are not powerful predictors of cognitive decline in our Chinese sample.Neurobiology of aging. 04/2014;