低频和罕见变异对血脂水平的影响。

The impact of low-frequency and rare variants on lipid levels.

作者信息

Surakka Ida, Horikoshi Momoko, Mägi Reedik, Sarin Antti-Pekka, Mahajan Anubha, Lagou Vasiliki, Marullo Letizia, Ferreira Teresa, Miraglio Benjamin, Timonen Sanna, Kettunen Johannes, Pirinen Matti, Karjalainen Juha, Thorleifsson Gudmar, Hägg Sara, Hottenga Jouke-Jan, Isaacs Aaron, Ladenvall Claes, Beekman Marian, Esko Tõnu, Ried Janina S, Nelson Christopher P, Willenborg Christina, Gustafsson Stefan, Westra Harm-Jan, Blades Matthew, de Craen Anton J M, de Geus Eco J, Deelen Joris, Grallert Harald, Hamsten Anders, Havulinna Aki S, Hengstenberg Christian, Houwing-Duistermaat Jeanine J, Hyppönen Elina, Karssen Lennart C, Lehtimäki Terho, Lyssenko Valeriya, Magnusson Patrik K E, Mihailov Evelin, Müller-Nurasyid Martina, Mpindi John-Patrick, Pedersen Nancy L, Penninx Brenda W J H, Perola Markus, Pers Tune H, Peters Annette, Rung Johan, Smit Johannes H, Steinthorsdottir Valgerdur, Tobin Martin D, Tsernikova Natalia, van Leeuwen Elisabeth M, Viikari Jorma S, Willems Sara M, Willemsen Gonneke, Schunkert Heribert, Erdmann Jeanette, Samani Nilesh J, Kaprio Jaakko, Lind Lars, Gieger Christian, Metspalu Andres, Slagboom P Eline, Groop Leif, van Duijn Cornelia M, Eriksson Johan G, Jula Antti, Salomaa Veikko, Boomsma Dorret I, Power Christine, Raitakari Olli T, Ingelsson Erik, Järvelin Marjo-Riitta, Thorsteinsdottir Unnur, Franke Lude, Ikonen Elina, Kallioniemi Olli, Pietiäinen Vilja, Lindgren Cecilia M, Stefansson Kari, Palotie Aarno, McCarthy Mark I, Morris Andrew P, Prokopenko Inga, Ripatti Samuli

机构信息

1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. [2] National Institute for Health and Welfare, Helsinki, Finland.

1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [2] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

出版信息

Nat Genet. 2015 Jun;47(6):589-97. doi: 10.1038/ng.3300. Epub 2015 May 11.

DOI:10.1038/ng.3300

PMID:25961943

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4757735/

Abstract

Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing.

摘要

通过千人基因组计划在62166个样本中对960万个遗传变异进行全基因组筛查，我们在93个基因座中鉴定出与脂质性状的关联，其中包括79个先前已鉴定基因座中的新的主效单核苷酸多态性（SNP）和10个新基因座、15个具有低频主效SNP的基因座和10个具有错义主效SNP的基因座，以及2个具有罕见变异积累的基因座。在六个基因座中，在脂质遗传学中具有既定功能的SNP（CELSR2、GCKR、LIPC和APOE）或具有预测损伤功能的候选错义突变（CD300LG和TM6SF2）解释了基因座关联。低频变异增加了解释的变异比例，特别是对于低密度脂蛋白胆固醇和总胆固醇。总之，我们的结果突出了低频变异在复杂性状中的影响，并表明推算提供了一种比重新测序更具成本效益的替代方法。