Details of Genomewide Association Results, Protocol, Statistical Analysis, and Additional References (Harlaar et al., 2014)

<b>Purpose </b>Researchers have previously shown that individual differences in measures of receptive language ability at age 12 are highly heritable. In the current study, the authors attempted to identify some of the genes responsible for the heritability of receptive language ability using a genome-wide association approach. <br><b>Method </b>The authors administered 4 Internet-based measures of receptive language (vocabulary, semantics, syntax, and pragmatics) to a sample of 2,329 twelve-year-olds for whom DNA and genome-wide genotyping were available. Nearly 700,000 single-nucleotide polymorphisms (SNPs) and 1 million imputed SNPs were included in a genome-wide association analysis of receptive language composite scores. <br><b>Results </b>No SNP associations met the demanding criterion of genome-wide significance that corrects for multiple testing across the genome ( <i>p</i> &lt; 5 × 10−8). The strongest SNP association did not replicate in an additional sample of 2,639 twelve-year-olds. <br><b>Conclusions </b>These results indicate that individual differences in receptive language ability in the general population do not reflect common genetic variants that account for more than 3% of the phenotypic variance. The search for genetic variants associated with language skill will require larger samples and additional methods to identify and functionally characterize the full spectrum of risk variants.

### 研究目的 <br>既往研究表明，12岁时接受性语言能力（receptive language ability）测量中的个体差异具有高度可遗传性。本研究中，作者尝试通过全基因组关联分析（genome-wide association approach）方法，识别部分与接受性语言能力可遗传性相关的基因。<br>### 研究方法 <br>研究人员对2329名12岁儿童的研究样本施测了4项基于互联网的接受性语言能力测评指标，涵盖词汇（vocabulary）、语义（semantics）、句法（syntax）与语用（pragmatics）四个维度；所有受试者均提供了DNA样本并完成了全基因组基因分型。针对接受性语言能力综合得分开展全基因组关联分析，共纳入近70万个单核苷酸多态性（single-nucleotide polymorphisms, SNPs）以及100万个推算单核苷酸多态性（imputed SNPs）位点。<br>### 研究结果 <br>未发现任何单核苷酸多态性位点达到校正全基因组范围内多重检验的严苛全基因组显著性标准（*p* < 5 × 10⁻⁸）。在额外纳入的2639名12岁儿童样本中，关联强度最高的单核苷酸多态性位点未能得到重复验证。<br>### 研究结论 <br>上述结果表明，普通人群中接受性语言能力的个体差异，并非由那些可解释表型变异超过3%的常见遗传变异所导致。寻找与语言技能相关的遗传变异，需要采用更大规模的样本与更多研究方法，以识别并从功能层面完整刻画各类风险变异的全貌。