澳大利亚昆士兰大学Loic Yengo等研究人员合作发现，遗传结构可调和复杂性状的连锁与关联研究。相关论文于2024年10月7日在线发表在《自然—遗传学》杂志上。

研究人员表示，连锁研究成功定位了单基因疾病的致病位点，但在研究常见疾病时大多未能奏效。相反，全基因组关联研究（GWAS）已经鉴定了数千个SNP与复杂性状之间的可重复关联，但仅捕捉到不到一半的总遗传力。

研究人员通过展示来自119000对兄弟姐妹的身高和体重指数（BMI）连锁信号与GWAS鉴定的位点共定位，调和了这两种方法。与多基因性一致，研究人员观察到了以下现象：全基因组范围内连锁检验统计量的膨胀；GWAS结果预测连锁信号；并且调整表型的多基因评分后连锁信号减弱。

最后，研究人员开发了一种基于重组率分层和兄弟姐妹间同源片段共享的无偏估算遗传力的方法，得出了身高遗传力为0.76 ± 0.05，BMI遗传力为0.55 ± 0.07。这些结果表明，GWAS鉴定的位点尚未解释的遗传力中，有相当一部分是多基因性的，并且富集在这些位点附近。

附：英文原文

Title: Genetic architecture reconciles linkage and association studies of complex traits

Author: Sidorenko, Julia, Couvy-Duchesne, Baptiste, Kemper, Kathryn E., Moen, Gunn-Helen, Bhatta, Laxmi, svold, Bjrn Olav, Mgi, Reedik, Ani, Alireza, Wang, Rujia, Nolte, Ilja M., Gordon, Scott, Hayward, Caroline, Campbell, Archie, Benjamin, Daniel J., Cesarini, David, Evans, David M., Goddard, Michael E., Haley, Chris S., Porteous, David, Medland, Sarah E., Martin, Nicholas G., Snieder, Harold, Metspalu, Andres, Hveem, Kristian, Brumpton, Ben, Visscher, Peter M., Yengo, Loic

Issue&Volume: 2024-10-07

Abstract: Linkage studies have successfully mapped loci underlying monogenic disorders, but mostly failed when applied to common diseases. Conversely, genome-wide association studies (GWASs) have identified replicable associations between thousands of SNPs and complex traits, yet capture less than half of the total heritability. In the present study we reconcile these two approaches by showing that linkage signals of height and body mass index (BMI) from 119,000 sibling pairs colocalize with GWAS-identified loci. Concordant with polygenicity, we observed the following: a genome-wide inflation of linkage test statistics; that GWAS results predict linkage signals; and that adjusting phenotypes for polygenic scores reduces linkage signals. Finally, we developed a method using recombination rate-stratified, identity-by-descent sharing between siblings to unbiasedly estimate heritability of height (0.76±0.05) and BMI (0.55±0.07). Our results imply that substantial heritability remains unaccounted for by GWAS-identified loci and this residual genetic variation is polygenic and enriched near these loci.

DOI: 10.1038/s41588-024-01940-2

Source: https://www.nature.com/articles/s41588-024-01940-2