Human genetic variants are associated with many traits through largely unknown mechanisms. Here, combining approximately 260,000 Japanese study participants, a Japanese-specific genotype reference panel and statistical fine-mapping, we identified 4,423 significant loci across 63 quantitative traits, among which 601 were new, and 9,406 putatively causal variants. New associations included Japanese-specific coding, splicing and noncoding variants, exemplified by a damaging missense variant rs730881101 in TNNT2 associated with lower heart function and increased risk for heart failure (P = 1.4 × 10⁻¹⁵ and odds ratio = 4.5, 95% confidence interval = 3.1–6.5). Putative causal noncoding variants were supported by state-of-art in silico functional assays and had comparable effect sizes to coding variants. A plausible example of new mechanisms of causal variants is an enrichment of causal variants in 3′ untranslated regions (UTRs), including the Japanese-specific rs13306436 in IL6 associated with pro-inflammatory traits and protection against tuberculosis. We experimentally showed that transcripts with rs13306436 are resistant to mRNA degradation by regnase-1, an RNA-binding protein. Our study provides a list of fine-mapped causal variants to be tested for functionality and underscores the importance of sequencing, genotyping and association efforts in diverse populations.

人类遗传变异通过基本未知的机制与许多性状相关联。在这里，结合大约 260,000 名日本研究参与者、日本特异性基因型参考面板和统计精细定位，我们确定了 63 个数量性状的 4,423 个重要位点，其中 601 个是新的，9,406 个推定的因果变异。新的关联包括日本特异性编码、剪接和非编码变体，例如TNNT2中与心脏功能降低和心力衰竭风险增加相关的破坏性错义变体rs730881101 （P = 1.4 × ^10-15 和比值比 = 4.5,95% 置信区间 = 3.1-6.5）。推定的因果非编码变异得到了最先进的计算机功能测定的支持，并且具有与编码变异相当的效应量。因果变异新机制的一个合理例子是 3' 非翻译区 （UTR） 中因果变异的富集，包括 IL6 中与促炎性状和预防结核病相关的日本特异性 rs13306436。我们实验表明，带有 rs13306436 的转录本对 RNA 结合蛋白 regnase-1 的 mRNA 降解具有抗性。我们的研究提供了一份精细定位的因果变异列表，用于测试功能，并强调了测序、基因分型和关联工作在不同人群中的重要性。