Beyond the lack of association between IFNG +874T>A polymorphism and personality traits in healthy Japanese subjects: Possible ethnic-specific effects

Tsuchimine et al. (2016) failed to replicate our initial finding on a link between the gamma-interferon (IFNG) +874T>A polymorphism (rs2430561) and harm avoidance, which was previously reported as one of the behavioral defenses against infection. Replication studies in genetic epidemiology are of fundamental relevance to establish the validity of genotype–phenotype associations. In addition to adequate statistical power and sound epidemiological design aimed at minimizing biases, suggested criteria for successful replication studies include: (1) same genetic variant, (2) same direction of association, (3) same definition of the phenotype, and (4) same ethnic group as reported in the discovery study. Despite the fact that Tsuchimine et al. (2016) tested the association of IFNG rs2430561 with personality traits on a larger sample size (N = 1411) respect to our study (N = 168), their data were collected on healthy Japanese subjects while our study was carried out on healthy American-Caucasians. Obviously, the two groups present numerous and fundamental differences, both at the genetic, cultural and socio-historical levels. At the genetic level, it is remarkable that the Japanese subjects display the lowest frequency of the infectious disease-high-risk IFNG +874 A-allele (7%) among the 26 populations sequenced by the 1000 Genomes Consortium. Using a set of six tagSNPs spanning the IFNG gene and its promoter region, we checked for differences in Linkage Disequilibrium (LD) and in haplotype frequencies between Japanese and American-Caucasian populations using data from the 1000 Genomes Consortium. As shown in Table 1, the distribution of IFNG haplotypes differs significantly between the two populations (P = 3.7 ! 10"24). Moreover, while the six SNPs belong to a unique LD block in American- Caucasians, the LD block in Japanese includes only the first four SNPs. The rs2430561-A allele is present in two common Caucasian-American haplotypes (H1 and H4), reaching a frequency of 42.4%, while it is present only in haplotype H1 among Japanese subjects with a frequency of 6.8%. This evidence is further supported by the study of Manry et al. (2011) that demonstrated population-specific positive selection at the IFNG locus. Thus, it is possible that in the Japanese population an IFNG polymorphism other than rs2430561 is operative.