A primate-specific (GCC) repeat in SMAD9 undergoes natural selection in humans and harbors unambiguous genotypes in late-onset neurocognitive disorder.

Abstract

Abstract Across numerous primate species and tissues, SMAD9 (SMAD Family Member 9) reaches the highest level of expression in the human brain. This gene contains a (GCC) short tandem repeat (STR) at the interval between + 1 and + 60 of the transcription start site, which is in the 1st percent of high-ranking (GCC)-repeats in respect of length. Here we sequenced this (GCC)-repeat in 396 Iranian individuals, consisting of late-onset neurocognitive disorder (NCD) (N = 181) and controls (N = 215). We detected two predominantly abundant alleles of 7 and 9 repeats, forming 96.2% of the allele pool. The ratio of the (GCC)7 and (GCC)9 alleles was in the reverse order in the NCD group versus controls (p = 0.005), resulting from excess of (GCC)7 in the NCD group (p = 0.003) and the 9-repeat in the controls (p = 0.01). Five genotypes, predominantly consisting of (GCC)7 and lacking (GCC)9 were detected in the NCD group only (p = 0.008). Those patients received probable diagnoses of Alzheimer’s disease and/or cerebrovascular dementia. Five genotypes consisting of (GCC)9 and lacking (GCC)7 were detected in the control group only (p = 0.002). The group-specific genotypes formed approximately 4% of the genotype pool in human samples studied. In conclusion, we propose natural selection and a novel locus for late-onset NCD at the SMAD9 (GCC)-repeat in humans. Although the percentage of individuals harboring the specific genotypes in each group was modest, those genotypes represent an underappreciated feature, which may enhance the perspective of disorders that are considered to be complex, and yet may be linked to unambiguous genotypes at certain STR loci.