Association of the Protocadherin gene cluster on chromosome 5q31 with extreme obesity in the NHLBI Family Heart Study (FamHS). I. B. Borecki1, M. F. Feitosa1, R. H. Myers2, J. B. Wilk2, Q. Zhang1, S. Ketkar1, D. M. Becker3, L. C. Becker3 1) Division of Statistical Genomics, Washington University School of Medicine, St Louis, MO; 2) Department of Neurology, Boston University, Boston, MA; 3) Division of General Internal Medicine, The Johns Hopkins University School of Medicine.

   The prevalence of obesity is increasing in the United States, particularly extreme obesity with its profound morbidities. We sought associations of common variants with extreme obesity (E_OB: BMI35.0 kg/m2; N = 63) versus controls (18<BMI<27.0 kg/m2; N=421) in the FamHS. Genotypes were assessed using the Illumina HumMap550 chip, and we imputed up to ~2.5 million SNPs based on HapMap Release 22 CEU phased haplotypes. Logistic regression, adjusting for age, sex, and field center effects that account for population stratification, was carried out, assuming additive SNP effects. The strongest association meeting genomewide significance occurred within the protocadherin (PCDH) gene cluster on 5q31 (p = 1.72e-08), in a broad region of linkage disequilibrium. In all, 48 SNPs in a vicinity spanning ~110 kb, showed evidence of association (P<1e-06); the minimum pairwise LD was D=1 (R2=0.75). For the SNP with strongest association, the minor allele was associated with an increased risk of E_OB (OR=4.43, CI:2.517.85, for each copy of the risk allele). Referring to the broader cohort of 1,000 subjects from which this sample of cases and controls was selected, the mean BMI was 27.5, 29.7, and 35.6 kg/m2 for genotypes with 0, 1, and 2 copies of the risk allele, respectively, and the SNP accounts for 2.2% of BMI variability. We attempted to validate these associations in an independent sample of 1,251 Caucasian subjects from the Genetic Study of Aspirin Responsiveness (GeneSTAR) study. We tested all 48 PCHD SNPs for association with either E_OB (N=163) or Obesity (N=403; OB: defined as BMI 30.0 kg/m2). While only 3/48 SNPs replicated for E_OB (p<0.01), virtually the entire region replicates with the OB trait with 37/48 SNPs significant at nominal levels; 9 additional SNPs within the focal LD region also were significant in the GeneSTAR data alone. This is a complex region including several closely-linked members of the protocadherin family, with overlapping reading frames, and with strong LD throughout, thus additional dissection of the region and the signal is needed. The protocadherins are members of the cadherin superfamily. While cadherins have a known role in cell adhesion, evidence suggests protocadherins are highly expressed in the central nervous system, and are involved in the modulation of synaptic transmission and the generation of specific synaptic connections, suggestive of a neuronal pathway influencing obesity.