KCTD8 gene and brain growth in adverse intrauterine environment: a genome-wide association study

Abstract

The most dramatic growth of the human brain occurs in utero and during the first 2 years of postnatal life. Genesis of the cerebral cortex involves cell proliferation, migration, and apoptosis, all of which may be influenced by prenatal environment. Here, we show that variation in KCTD8 (potassium channel tetramerization domain 8) is associated with brain size in female adolescents (rs716890, P = 5.40 × 10(-09)). Furthermore, we found that the KCTD8 locus interacts with prenatal exposure to maternal cigarette smoking vis-à-vis cortical area and cortical folding: In exposed girls only, the KCTD8 locus explains up to 21% of variance. Using head circumference as a proxy of brain size at 7 years of age, we have replicated this gene-environment interaction in an independent sample. We speculate that KCTD8 might modulate adverse effects of smoking during pregnancy on brain development via apoptosis triggered by low intracellular levels of potassium, possibly reducing the number of progenitor cells.

Figure 1.

Top: results of the genome-wide analysis of brain volume in female adolescents, as shown by WGAviewer, version 2 (Ge et al. 2008). The top SNPs are indicated by numbers 1 through 11; SNPs 2,3, 5, and 6 (indicated in red) reached genome-wide significance (P < 5.0 × 10⁻⁰⁸). Bottom: LD structure of the identified SNPs, as examined with HaploView 4.2 (Barrett et al. 2005) and indicated by D′ values. Numbers identify the same SNPs shown in the top part of this figure.

Figure 2.

Age-adjusted values (mean ± standard error) of brain volume (top), total cortical area (middle), and cortical folding (bottom) in female adolescents exposed (left column) and not exposed (right column) to maternal cigarette smoking during pregnancy, all plotted as a function of the KCTD8 genotype (rs716890; GG, GT, and TT genotypes; G, guanine; T, thymine). The amount of variance (r²) explained by the genotype and statistical significance of the genotype effect of each phenotype are indicated. Note that we observed significant interaction between the KCTD8 genotype (rs716890) and “exposure” on total cortical area and cortical folding but not on brain volume.