Data from: DNA and RNA-sequence based GWAS highlights membrane-transport genes as key modulators of milk lactose content

Lactose provides an easily-digested energy source for neonate mammals, and is the primary carbohydrate in milk. Lactose is also a key component of many human food products, though compared to analyses of other milk components, the genetic control of lactose has been little studied. Here we present the first GWAS of milk lactose concentration and yield, investigated in a population of 12,000 taurine dairy cattle. We detail 27 QTL spanning these traits, and subsequently validate the effects of 26 of these loci in a separate population of 18,000 cows. We next present data implicating causative genes and variants for these QTL. Fine mapping of these regions using imputed, whole genome sequence-resolution genotypes reveals protein-coding candidate causative variants affecting the ABCG2, DGAT1, STAT5B, KCNH4, NPFFR2 and RNF214 genes. Eleven of the remaining QTL appear to be driven by regulatory effects, suggested by the presence of co-locating, co-segregating eQTL discovered using mammary RNA sequence data representing a population of 357 lactating cows. Pathway analysis of genes representing all lactose-associated loci shows significant enrichment of genes located to the endoplasmic reticulum, with functions related to ion channel activity mediated through the LRRC8C, P2RX4, KCNJ2 and ANKH genes. Together, these findings highlight novel candidate genes and variants involved in milk lactose regulation, whose impacts on facilitated and active membrane transport mechanisms reinforce the key osmo-regulatory roles of lactose in milk.

乳糖是新生哺乳动物易于消化吸收的能量来源，亦是乳汁中的核心碳水化合物组分。同时，乳糖也是诸多人类食品的关键成分，但相较于其他乳汁成分的相关研究，乳糖的遗传调控机制迄今鲜有深入探究。本研究针对12000头乳用普通牛种群，首次开展了乳汁乳糖浓度与产乳糖量的全基因组关联分析（Genome-Wide Association Study, GWAS）。我们共鉴定出覆盖这两类性状的27个数量性状位点（Quantitative Trait Locus, QTL），随后在包含18000头奶牛的独立种群中，验证了其中26个位点的遗传效应。后续研究中，我们通过多组学数据揭示了这些QTL的候选致病基因与致病变异。利用插补获得的全基因组测序分辨率基因型对上述QTL区域进行精细定位，发现了多个影响ABCG2、DGAT1、STAT5B、KCNH4、NPFFR2及RNF214基因的蛋白质编码型候选致病变异。剩余的11个QTL的遗传效应似乎由调控机制驱动：通过对357头泌乳奶牛的乳腺RNA测序数据开展分析，我们鉴定到了共定位且共分离的表达数量性状位点（expression Quantitative Trait Locus, eQTL），这一结果为上述调控驱动假说提供了支持依据。对所有乳糖相关位点对应的基因进行通路富集分析，结果显示内质网（endoplasmic reticulum）定位基因呈现显著富集态势，且这些基因的功能与LRRC8C、P2RX4、KCNJ2及ANKH基因介导的离子通道活性密切相关。综上，本研究揭示了参与乳汁乳糖调控的全新候选基因与变异，这些基因通过易化转运与主动膜转运机制发挥功能，进一步印证了乳糖在乳汁中所发挥的关键渗透压调节（osmo-regulatory）作用。