Common variant heritability has been widely reported to be concentrated in variants within cell-type-specific noncoding functional annotations, but little is known about low-frequency variant functional architectures. We partitioned the heritability of both low-frequency (0.5%≤MAF<5%) and common (MAF≥5%) variants in 40 UK Biobank traits across a broad set of functional annotations. We determined that non-synonymous coding variants explain 17±1% of low-frequency variant heritability ( ) versus 2.1±0.2% of common variant heritability ( ). Cell-type-specific noncoding annotations that were significantly enriched for of corresponding traits were similarly enriched for for most traits, but more enriched for brain-related annotations and traits. For example, H3K4me3 marks in brain dorsolateral prefrontal cortex explain 57±12% of vs. 12±2% of for neuroticism. Forward simulations confirmed that low-frequency variant enrichment depends on the mean selection coefficient of causal variants in the annotation, and can be used to predict effect size variance of causal rare variants (MAF<0.5%).
展开▼
机译:据普遍报道,常见的变异性遗传力集中在特定于细胞类型的非编码功能注释内的变异中,但对低频变异功能结构知之甚少。我们将40个英国生物库特征中的低频(0.5%≤MAF<5%)和常见(MAF≥5%)变异体的遗传力划分为一系列广泛的功能注释。我们确定非同义的编码变体解释了低频变体遗传力的17±1%( h mi> l mi> f mi> mrow> 2 mn> msubsup> mrow> math>),而不是普通变体遗传力的2.1±0.2%(展开▼