Multi-ancestry LPA KIV-2 haplotype analysis and imputation

Lipoprotein(a) [Lp(a)] is a lipid particle in human blood. Its blood levels are the most significant genetic risk factor for cardiovascular diseases in the general population. They are primarily determined by a complex interplay of genetic variants in the LPA gene. A large portion of the gene sequence is located in an exceptionally complicated genomic region composed of large, repetitive and nearly identical elements (a so-called "VNTR region). Each of the two gene copies in the human genome contains up to approximately 40 repeats of a so-called "KIV-2" gene element. The number of KIV-2 repeats determines the personal baseline level of Lp(a) in the blood. However, the KIV-2 region also hides many genetic variants, which modify the effect of the KIV-2 number and thus significantly affect the individual Lp(a) levels. The details of this interplay are complex and multifaceted. As a result, although Lp(a) levels are regulated by the LPA gene in all individuals, the average Lp(a) levels can vary tenfold between different ancestries, and the individual Lp(a) levels can vary even 1000- fold between individuals. Consequently, the cardiovascular risk conferred by Lp(a) varies greatly between individuals and between populations. These complex gene structures and the intricate interplay between the length of the VNTR and individual mutations in the LPA gene significantly complicate studies of the genetics of Lp(a). Therefore, the exact genetic mechanisms that determine the huge variability in Lp(a) levels between individuals and between ancestries are not well understood, yet. As part of this FWF-funded project, the genetic variability in this complex region will be investigated in a diverse population of approximately 1900 individuals from four continents using high-precision single-molecule sequencing. Based on these reference data, we will develop various methods for the simple reconstruction of this complex gene structure and for determining mutation patterns hidden in the KIV-2 at scale. These methods shall be subsequently applicable easily also by other scientists to their own study populations. This promises new tools for genetic Lp(a) research, new insights into the genetic regulation of Lp(a) and its enormous variability between populations and a new approach to studying complex, repetitive genomic regions in general.

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