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Background  Lactose provides an easily-digested energy source for neonates, and is the primary carbohydrate in milk in most species. Bovine lactose is also a key component of many human food products. However, compared to analyses of other milk components, the genetic control of lactose has been little studied. Here we present the first GWAS focussed on analysis of milk lactose traits.    Results  Using a discovery population of 12,000 taurine dairy cattle, we detail 27 QTL for lactose concentration and yield, and subsequently validate the effects of 26 of these loci in a distinct 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 from a population of 357 lactating cows. Pathway analysis of genes representing all lactose-associated loci shows significant enrichment of genes located in the endoplasmic reticulum, with functions related to ion channel activity mediated through the  LRRC8C ,  P2RX4 ,  KCNJ2  and  ANKH  genes. A number of the validated QTL are also found to be associated with additional milk volume, fat and protein phenotypes.    Conclusions  Overall, these findings highlight novel candidate genes and variants involved in milk lactose regulation, whose impacts on membrane transport mechanisms reinforce the key osmo-regulatory roles of lactose in milk.    Electronic supplementary material  The online version of this article (doi:10.1186/s12864-017-4320-3) contains supplementary material, which is available to authorized users.

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