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Phosphodiesterase 8B Gene Variants Are Associated with Serum TSH Levels and Thyroid Function

Summary: ARTICLE
Phosphodiesterase 8B Gene Variants Are Associated
with Serum TSH Levels and Thyroid Function
Lisette Arnaud-Lopez,1,11 Gianluca Usala,2,11 Graziano Ceresini,3 Braxton D. Mitchell,4
Maria Grazia Pilia,2 Maria Grazia Piras,2 Natascia Sestu,2 Andrea Maschio,2 Fabio Busonero,2
Giuseppe Albai,2 Mariano Dei,2 Sandra Lai,2 Antonella Mulas,2 Laura Crisponi,2 Toshiko Tanaka,5
Stefania Bandinelli,6 Jack M. Guralnik,7 Angela Loi,2 Lenuta Balaci,2 Gabriella Sole,2 Alessia Prinzis,8
Stefano Mariotti,8 Alan R. Shuldiner,4,9 Antonio Cao,2 David Schlessinger,1 Manuela Uda,2
Gonc¸alo R. Abecasis,10 Ramaiah Nagaraja,1 Serena Sanna,2 and Silvia Naitza2,*
Thyroid-stimulating hormone (TSH) controls thyroid growth and hormone secretion through binding to its G protein-coupled receptor
(TSHR) and production of cyclic AMP (cAMP). Serum TSH is a sensitive indicator of thyroid function, and overt abnormalities in thyroid
function lead to common endocrine disorders affecting ~10% of individuals over a life span. By genotyping 362,129 SNPs in 4,300 Sar-
dinians, we identified a strong association (p ¼ 1.3 3 10À11
) between alleles of rs4704397 and circulating TSH levels; each additional
copy of the minor A allele was associated with an increase of 0.13 mIU/ml in TSH. The single-nucleotide polymorphism (SNP) is located
in intron 1 of PDE8B, encoding a high-affinity cAMP-specific phosphodiesterase. The association was replicated in 4,158 individuals,
including additional Sardinians and two genetically distant cohorts from Tuscany and the Old Order Amish (overall p value ¼ 1.9 3
). In addition to association of TSH levels with SNPs in PDE8B, our genome scan provided evidence for association with
PDE10A and several biologically interesting candidates in a focused analysis of 24 genes. In particular, we found evidence for association


Source: Abecasis, Goncalo - Department of Biostatistics, University of Michigan


Collections: Biology and Medicine; Mathematics