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TheTHBS4gene encodes a glycoprotein involved in inflammatory responses and synaptogenesis.THBS4is expressed at higher levels in the brain of humans compared with nonhuman primates, and the protein accumulates in β-amyloid plaques. We analyzedTHBS4genetic variability in humans and show that two haplotypes (hap1 and hap2) are maintained by balancing selection and modulateTHBS4expression in lymphocytes. Indeed, the balancing selection region covers a predicted transcriptional enhancer. In humans, but not in macaques and chimpanzees,THBS4brain expression increases with age, and variants in the balancing selection region interact with sex in influencingTHBS4expression (pinteraction = 0.038), with hap1 homozygous females showing lowest expression. In Alzheimer disease (AD) patients, significant interactions between sex andTHBS4genotype were detected for peripheral gray matter (pinteraction = 0.014) and total gray matter (pinteraction = 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 inTHBS4is likely represented by one or more variants that regulate tissue-specific and sex-specific gene expression. The selection signature associated withTHBS4might not be related to AD pathogenesis, but rather to inflammatory responses.