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Long‐Standing Balancing Selection in the THBS 4 Gene: Influence on Sex‐Specific Brain Expression and Gray Matter Volumes in Alzheimer Disease
Author(s) -
Cagliani Rachele,
Guerini Franca R.,
RubioAcero Raquel,
Baglio Francesca,
Forni Diego,
Agliardi Cristina,
Griffanti Ludovica,
Fumagalli Matteo,
Pozzoli Uberto,
Riva Stefania,
Calabrese Elena,
Sikora Martin,
Casals Ferran,
Comi Giacomo P.,
Bresolin Nereo,
Cáceres Mario,
Clerici Mario,
Sironi Manuela
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22301
Subject(s) - biology , balancing selection , gene expression , gene , genetics , selection (genetic algorithm) , enhancer , genetic variation , artificial intelligence , computer science
The THBS4 gene encodes a glycoprotein involved in inflammatory responses and synaptogenesis. THBS4 is expressed at higher levels in the brain of humans compared with nonhuman primates, and the protein accumulates in β‐amyloid plaques. We analyzed THBS4 genetic variability in humans and show that two haplotypes (hap1 and hap2) are maintained by balancing selection and modulate THBS4 expression in lymphocytes. Indeed, the balancing selection region covers a predicted transcriptional enhancer. In humans, but not in macaques and chimpanzees, THBS4 brain expression increases with age, and variants in the balancing selection region interact with sex in influencing THBS4 expression ( p interaction = 0.038), with hap1 homozygous females showing lowest expression. In A lzheimer disease ( AD ) patients, significant interactions between sex and THBS4 genotype were detected for peripheral gray matter ( p interaction = 0.014) and total gray matter ( p interaction = 0.012) volumes. Similarly to the gene expression results, the interaction is mainly mediated by hap1 homozygous AD females, who show reduced volumes. Thus, the balancing selection target in THBS4 is likely represented by one or more variants that regulate tissue‐specific and sex‐specific gene expression. The selection signature associated with THBS4 might not be related to AD pathogenesis, but rather to inflammatory responses.