Evaluation of the Metabochip Genotyping Array in African Americans and Implications for Fine Mapping of GWAS-Identified Loci: The PAGE Study

The Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5×10−11), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2×10−36). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.代谢芯片（Metabochip）是一款定制化基因分型芯片，专为代谢、心血管及人体测量性状位点的验证与精细定位而设计，其包含从千人基因组计划（1000 Genomes Project）中鉴定得到的低频变异集。该芯片共包含196725个单核苷酸多态性位点（Single Nucleotide Polymorphism, SNP），分布于257个基因组区域内。我们在5863名非裔美国人样本中对该代谢芯片开展了性能评估，结果显示89%的SNP位点通过了严格的质量控制，分型成功率达99.9%。我们通过两个实例展示了该代谢芯片在非洲血统人群中进行性状位点精细定位的应用价值：在CELSR2/PSRC1/SORT1基因区域，我们发现与低密度脂蛋白胆固醇（Low-Density Lipoprotein Cholesterol, LDL-C）关联最强的SNP位点为rs12740374（P=3.5×10⁻¹¹）；由于连锁不平衡程度较高，该位点在欧洲血统人群的样本中与多个SNP位点无法区分，其独特的关联信号佐证了此前其他功能研究的结论，即该位点在低密度脂蛋白胆固醇代谢中发挥因果作用。在CETP基因区域，我们发现rs17231520位点与高密度脂蛋白胆固醇（High-Density Lipoprotein Cholesterol, HDL-C）存在显著关联（P=7.2×10⁻³⁶），该位点在非裔美国人中的风险等位基因频率为0.07；该变异在欧洲人群中极为罕见，且未被常规全基因组关联研究（Genome-Wide Association Study, GWAS）芯片所覆盖，但此前一项单基因研究已在非裔美国人中鉴定出该位点与高密度脂蛋白胆固醇代谢相关联。本研究的两项结果——一项缩小了风险区间，另一项发现了欧洲人群中未被报道的关联变异——证实了针对常见及罕见变异开展高密度基因分型，有助于在非裔美国人样本中实现性状位点的精细定位。