Selective genotyping with epistasis can be utilized for a major quantitative trait locus mapping in hypertension in rats

Epistasis used to be considered an obstacle in mapping quantitative trait l oci (QTL) despite its significance. Numerous epistases have proved to be in volved in quantitative genetics. We established a backcross model that demo nstrates a major QTL for hypertension (Ht). Seventy-eight backcrossed rats (BC), derived from spontaneously hypertensive rats (SHR) and normotensive F ischer 344 rats, showed bimodal distribution of systolic blood pressure (BP ) values and a phenotypic segregation ratio consistent with 1:1. In this ba ckcross analysis, sarco(endo)plasmic reticulum Ca2+-dependent ATPase (Serca ) II heterozygotes showed widespread bimodality in frequency distribution o f BP values and obviously demonstrated Ht. First, in genome-wide screening, Mapmaker/QTL analysis mapped Ht at a locus between D1Mgh8 and D1Mit4 near Sa in all 78 BC. The peak logarithm of the odds (LOD) score reached 5.3. Se cond, Serca II heterozygous and homozygous BC were analyzed separately usin g Mapmaker/QTL. In the 35 Serca II heterozygous BC, thc peak LOD score was 3.8 at the same locus whereas it did not reach statistical significance in the 43 Serca II homozygotes. Third, to map Ht efficiently, we selected 18 S erca II heterozygous BC with 9 highest and 9 lowest BP values. In these 18 BC, the peak LOD score reached 8.1. In 17 of the 18, D1Mgh8 genotypes (homo or hetero) qualitatively cosegregated with BP phenotypes (high or low) (P < 0.0001, by chi-square analysis). In conclusion, selective genotyping with epistasis can be utilized for a major QTL mapping near Sa on chromosome 1 in SHR.