Common variants at 6q22 and 17q21 are associated with intracranial volume

Abstract

During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 × 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 × 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10(-3) for 6q22 and 1.2 × 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.

Figure 1

a and b. Genome-wide signal intensity (Manhattan) plots showing the individual p-values (based on the fixed-effects meta-analysis) against their genomic position for brain volume (a) and intracranial volume (b). Within each chromosome, shown on the x-axis, the results are plotted left to right from the p-terminal end. The horizontal lines indicate thresholds for p=10⁻⁴, p=10⁻⁵, and p=5*10⁻⁸ (genome-wide significant).

Figure 1

a and b. Genome-wide signal intensity (Manhattan) plots showing the individual p-values (based on the fixed-effects meta-analysis) against their genomic position for brain volume (a) and intracranial volume (b). Within each chromosome, shown on the x-axis, the results are plotted left to right from the p-terminal end. The horizontal lines indicate thresholds for p=10⁻⁴, p=10⁻⁵, and p=5*10⁻⁸ (genome-wide significant).

Figure 2. a and b. Regional plots for the genome-wide significant associations with intracranial volume

All SNPs (circles) are plotted with their meta-analysis p-values against their genomic position. Circles are color-coded according to their linkage disequilibrium with the top SNP (purple rectangle) as follows: r²<0.2 darkblue; 0.2<r²<0.4 lightblue; 0.4<r²<0.6 green; 0.6<r²<0.8 orange; 0.8<r² red. The blue line at the bottom of the graph represents the estimated recombination rates. Gene annotations are shown as the black arrows. We note that several copy number variations have been reported at chr6q22, the closest of which are downstream of rs4273712 at position 127124970-127135701 and 127136191-127141042.

Figure 2. a and b. Regional plots for the genome-wide significant associations with intracranial volume

All SNPs (circles) are plotted with their meta-analysis p-values against their genomic position. Circles are color-coded according to their linkage disequilibrium with the top SNP (purple rectangle) as follows: r²<0.2 darkblue; 0.2<r²<0.4 lightblue; 0.4<r²<0.6 green; 0.6<r²<0.8 orange; 0.8<r² red. The blue line at the bottom of the graph represents the estimated recombination rates. Gene annotations are shown as the black arrows. We note that several copy number variations have been reported at chr6q22, the closest of which are downstream of rs4273712 at position 127124970-127135701 and 127136191-127141042.