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论文题目: Rare and low-frequency coding variants alter human adult height
英文论文题目: Rare and low-frequency coding variants alter human adult height
第一作者: Marouli, E; Graff, M; Medina-Gomez, C; Lo, KS; Wood, AR; Kjaer, TR; Fine, RS; Lu, YC; Schurmann, C; Highland, HM; Rueger, S; et al.
英文第一作者: Marouli, E; Graff, M; Medina-Gomez, C; Lo, KS; Wood, AR; Kjaer, TR; Fine, RS; Lu, YC; Schurmann, C; Highland, HM; Rueger, S; et al.
联系作者: Deloukas, P (reprint author), Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London EC1M 6BQ, England.
英文联系作者: Deloukas, P (reprint author), Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London EC1M 6BQ, England.
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发表年度: 2017
卷: 542
期: 7640
页码: 186-190
摘要: Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
英文摘要: Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
刊物名称: NATURE
英文刊物名称: NATURE
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学科: Multidisciplinary Sciences
英文学科: Multidisciplinary Sciences
影响因子: 40.137
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论文类别: Article
英文论文类别: Article
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