12岁时的阅读和数学能力之间的相关性有很大的遗传成分外文翻译资料

The correlation between reading and mathematics ability at age twelve has a substantial genetic component

Introduction

Understanding the aetiology of complex cognitive traits such as reading and mathematics ability is essential for helping children achieve their potential. These traits are highly heritable and have been shown to associate with quality of life including wealth and life expectancy. In spite of their importance and well-established heritability, much remains to be understood about the genetic architecture of cognitive abilities and the genetic component to the correlation between them.

It has been shown that population variation in cognitive abilities shares a substantial genetic component with learning difficulties such as dyslexia and dyscalculia (defined here as the low extreme of the distribution). These difficulties affect more than 10% of the population of English-speaking countries, with undiagnosed problems costing economies billions of dollars per year, as well as the less well-documented human cost of missed opportunities. Dyslexia is by far the most frequently diagnosed form of learning difficulty in school-age children, it shows strong stability across childhood and adolescence, and frequently co-occurs with other childhood learning difficulties and psychopathologies. Although much less is known about dyscalculia, numeracy is as much a requirement as literacy in our increasingly technological world.

Dyslexia was one of the first traits studied using QTL sib-pair linkage analysis, and although it has been proven to be difficult to identify the genes responsible for these linkages, several candidate genes are under scrutiny. The first steps towards genome-wide association studies (GWAS) of reading and mathematics ability, using pooled DNA on microarrays, concluded that it is likely that no common genetic variants of large effect influence either trait. Until recently, no common variants associated with the normal range of cognitive traits have been discovered with compelling levels of evidence, although some candidates have been reported.

Here we conduct a GWAS of Reading and Mathematics abilities in a sample of ~3,000 twin pairs. We find no replicable loci with convincing levels of evidence for association, consistent with a substantially polygenic contribution of genetics to these traits. Using bivariate twin- and population-level models, we estimate the heritability and genetic correlation between the two traits. We find a high genetic correlation (around 70%), indicating substantial pleiotropy, and accounting for a large proportion of phenotypic correlation.

Results

As part of the Wellcome Trust Case-Control Consortium 2 (WTCCC2), in collaboration with the Twins Early Development Study (TEDS), we performed a GWAS using 2,794 unrelated members of monozygotic (MZ) and dizygotic (DZ) twin pairs, measured for their reading and mathematics ability using a combination of web- and phone-based tests at age twelve. The scores were combined across tests and adjusted for age, while gender was used as a covariate in the analyses. Using genotype imputation we performed association analysis for 1,588,650 autosomal markers with reading and mathematics scores separately (see Methods). We followed up the strongest signals of association (P_GWASlt;5 times; 10^minus;5; reading, N=2,243; mathematics, N=2,772) in a further 2,153 individuals, some of whom were co-twins of individuals in the discovery data. One region on chromosome 19 (rs349045) achieved a P-value of 9.63 times; 10^minus;9 (Merlin, N=6,061) for reading ability in the joint analysis of discovery and replication data. However, this association failed to replicate using a related phenotype (the Test of Word-Reading Efficiency (TOWRE)—one of four reading tests from the TEDS analysis) in the Avon Longitudinal Study of Parents and Children (ALSPAC, N=2,077). The results for the GWAS are shown in Supplementary Figs 1 and 2 and Supplementary Tables 1 and 2. The results from loci previously reported to be associated with reading or mathematics ability or difficulties are reported in Supplementary Table 3.

One explanation for the lack of compelling evidence for association at individual single-nucleotide polymorphisms (SNPs), despite large sample sizes and high heritability estimates, is that the traits studied here are substantially polygenic, with each variant having a small effect. Recent studies have demonstrated that the genetic variants that determine measures of intelligence early and late in life overlap. In our data, standardised reading and mathematics scores show a high correlation, r=0.60. This is perhaps unsurprising given that many environmental influences (for example, parenting, schooling and socio-economic factors) will impact on both reading and mathematics ability. Twin studies have also identified a genetic contribution to the correlation. Our data provide the opportunity to clarify the contribution of genetics to the strong correlation in these cognitive abilities using both twin and molecular data in the same sample.

To investigate the genetic contribution to the correlation, we first fit a bivariate version of the classical twin model using both MZ and DZ twin pairs for whom the reading and mathematics scores were available (Methods and Fig. 1). This method does not use the genotype data, but assumes that genetic relatedness at the variants that affect the traits follows average relatedness of twins (one half for DZ twins and one for MZ twins). The approach estimates

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