Multiple blood pressure loci with opposing blood pressure effects on rat chromosome 1 in a homologous region linked to hypertension on human chromosome 15

Abstract

Genetic dissection of blood pressure (BP) quantitative trait loci (QTLs) in rats has facilitated the fine-mapping of regions linked to the inheritance of hypertension. The goal of the current study was to further fine-map one such genomic region on rat chromosome 1 (BPQTL1b1), the homologous region of which on human chromosome 15 harbors BP QTLs, as reported by four independent studies. Of the six substrains constructed and studied, the systolic BP of two of the congenic strains were significantly lower by 36 and 27 mm Hg than that of the salt-sensitive (S) rat (P < 0.0001, P = 0.0003, respectively). The congenic segments of these two strains overlapped between 135.12 and 138.78 Mb and contained eight genes and two predicted miRNAs. None of the annotations had variants within expressed sequences. These data taken together with the previous localization resolved QTL1b1 with a 70% improvement from the original 7.39 Mb to the current 2.247 Mb interval. Furthermore, the systolic BP of one of the congenic substrains was significantly higher by 20 mm Hg (P < 0.0001) than the BP of the S rat. The limits of this newly identified QTL with a BP increasing effect (QTL1b1a) were between 134.12 and 135.76 Mb, spanning 1.64 Mb, containing two protein-coding genes, Mctp2 and Rgma, and a predicted miRNA. There were four synonymous variants within Mctp2. These data provide evidence for two independent BP QTLs with opposing BP effects within the previously identified BP QTL1b1 region. Additionally, these findings illustrate the complexity underlying the genetic mechanisms of BP regulation, wherein inherited elements beyond protein-coding sequences or known regulatory regions could be operational.

Further dissection of QTLs for salt-induced stroke and identification of candidate genes in the stroke-prone spontaneously hypertensive rat

“…This might be due to multiple QTLs affecting the stroke latency in this region as suggested by the broad peak observed in this QTL 6 . Similar observations were commonly observed in attempts to narrow down QTL regions using subcongenic rats 7 – 9 .…”

Contrasting genetic architectures in different mouse reference populations used for studying complex traits

“…The substantial number of QTLs detected with congenic, subcongenic, and subsub-congenic strains suggests that many additional QTLs could be systematically detected by further increasing the number of congenic strains (Shao et al 2010;Yazbek et al 2011). Evidence from other species such as yeast, rats, and humans also shows that QTLs harbor multiple tightly linked sub-QTLs and causative genetic variants (Steinmetz et al 2002;Nejentsev et al 2007;Lango Allen et al 2010;Ehret et al 2012;Flister et al 2013;Mell et al 2015).…”

Genome-Wide Association Studies in Drug-Induced Liver Injury: Step Change in Understanding the Pathogenesis

“…59 The gene encodes a transmembrane protein belonging to the multiple C2 domain family implicated in intercellular signal transduction and synapse function. This gene has also been found to be important for cardiogenesis and recently suggested to be important for blood pressure regulation, 60 but a direct pathogenic role in DILI is not apparent. A polymorphism near CAAP1 was also found to associate with flucloxacillin DILI.…”