Association of the lactase persistence haplotype block with disease risk in populations of european descent

Authors: JOSLIN, SHANNON - University Of California, Davis; DURBIN-JOHNSON, BLYTHE - University Of California, Davis; BRITTON, MONICA - University Of California, Davis; SETTLES, MATTHEW - University Of California, Davis; KORF, IAN - University Of California, Davis; Lemay, Danielle

Submitted to: Frontiers in Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/8/2020
Publication Date: 10/29/2020
Citation: Joslin, S.E., Durbin-Johnson, B.P., Britton, M.T., Settles, M.L., Korf, I., Lemay, D.G. 2020. Association of the lactase persistence haplotype block with disease risk in populations of European descent. Frontiers in Genetics. 11. Article: 558762. https://doi.org/10.3389/fgene.2020.558762.
DOI: https://doi.org/10.3389/fgene.2020.558762

Interpretive Summary: Among people of European descent, the ability to digest lactose into adulthood is conferred by one genetic variant. This genetic variant was so advantageous that it rapidly spread throughout Europe, suggesting that not-so-great variants in the neighborhood of the genetic variant may have hitchhiked along with it. Therefore, the objective of the current study was to determine the amount of shared DNA in this region and how this may have impacted human health. We estimated the amount of shared DNA to be 1.9 Mbp containing up to 9 protein-coding genes and a microRNA. We then used data from three different large-scale consortiums to evaluate the impact of this shared DNA on prostate cancer status, cardiovascular disease status, and bone mineral density. Despite the fact that previous work demonstrated that the shared DNA had increased deleterious mutations, our results suggested that these mutations have little effect on modern human health.

Technical Abstract: Among people of European descent, the ability to digest lactose into adulthood arose via strong positive selection of a highly advantageous allele encompassing the lactase gene. Lactose-tolerant and intolerant individuals may have different disease risks due to the shared genetics of their haplotype block. Therefore, the overall objective of the current study was to assess the genetic association of the lactase persistence (LP) haplotype to disease risk. Using data from the 1000Genomes project, we estimated the size of the LP haplotype block to be 1.9 Mbp containing up to 9 protein-coding genes and a microRNA. We selected health phenotypes most likely to be impacted by the LP allele: prostate cancer status, cardiovascular disease status, and bone mineral density. We used summary statistics from large genome-wide metanalyses—32,965 subjects in the GEFOS consortium data, 140,306 subjects in the PRACTICAL consortium data and 184,305 subjects in the CARDIoGRAMplusC4D data—to evaluate whether the LP haplotype was associated with these phenotypes. We applied several types of statistical tests to determine the impact of the LP haplotype. Despite the fact that previous work demonstrated that the LP haplotype block harbors increased deleterious mutations, these results suggest little effect on modern human health.