Body Mass Index Quantitative Trait Locus 12

A number sign (#) is used with this entry because of evidence that susceptibility to obesity can be influenced by variation in the PCSK1 gene (162150).

For a phenotypic description and a discussion of genetic heterogeneity of body mass index (BMI), see 606641.

Molecular Genetics

Four independent genomewide linkage studies, 2 of which were done in independent sets of individuals of French European ancestry, delineated a common 5.6-Mb interval on chromosome 5q linked with obesity-associated traits (Hager et al., 1998; Chagnon et al., 2001; Bell et al., 2004; Chen et al., 2005). This interval contains the PCSK1 gene, which encodes an enzyme expressed in neuroendocrine cells that converts prohormones into functional key hormones that regulate central and/or peripheral energy metabolism. Mutations in PCSK1 cause proprotein convertase-1/3 deficiency (600955), a syndrome characterized by obesity (601665) and small intestinal dysfunction. To assess the contribution of PCSK1 to polygenic obesity risk, Benzinou et al. (2008) genotyped tag SNPs in a total of 13,659 individuals of European ancestry from 8 independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D (162150.0005), and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity.