To identify genes contributing to hyperthyrotropinemia and clinical hypothyroidism, we performed linkage analysis on 1,258 individuals from three semi-isolated Alpine villages. Cases were defined based on TSH levels (TSH ≥ 4.6 mU/L and TSH > 3.0 mU/L) and medical treatment while having normal/low fT4 levels. Two peaks on chromosomes 3q28-29 and 6q26-27 were identified. SNP- and gene-based association under the linkage peaks identified signals within the PDE10A and DACT2 genes amongst others. Previous population studies have suggested association of variants in PDE10A with TSH levels. Our results indicate the presence of variants in the region of these genes capable of contributing to pathological disruption of the hypothalamus-pituitary-thyroid axis. (By Claudia Volpato, PhD, http://jmg.bmj.com/content/early/2011/06/20/jmg.2010.088583.abstract?papetoc )