A whole-genome scan for 24-hour respiration rate: a major locus at 10q26 influences respiration during sleep.

Identification of genes causing variation in daytime and nighttime respiration rates could advance our understanding of the basic molecular processes of human respiratory rhythmogenesis. This could also serve an important clinical purpose, because dysfunction of such processes has been identified as critically important in sleep disorders. We performed a sib-pair-based linkage analysis on ambulatory respiration rate, using the data from 270 sibling pairs who were genotyped at 374 markers on the autosomes, with an average distance of 9.65 cM. Uni- and multivariate variance-components-based multipoint linkage analyses were performed for respiration rate during three daytime periods (morning, afternoon, and evening) and during nighttime sleep. Evidence of linkage was found at chromosomal locations 3q27, 7p22, 10q26, and 22q12. The strongest evidence of linkage was found for respiration rate during sleep, with LOD scores of 2.36 at 3q27, 3.86 at 10q26, and 1.59 at 22q12. In a simultaneous analysis of these three loci, >50% of the variance in sleep respiration rate could be attributed to a quantitative-trait loci near marker D10S1248 at 10q. Genes in this area (GFRA1, ADORA2L, FGR2, EMX2, and HMX2) can be considered promising positional candidates for genetic association studies of respiratory control during sleep.