Common variants at 12q15 and 12q24 are associated with infant head circumference

Abstract

To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 × 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height, their effects on infant head circumference were largely independent of height (P = 3.8 × 10(-7) for rs7980687 and P = 1.3 × 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume, Parkinson's disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.

Figure 1

Directly genotyped and imputed SNPs are plotted using filled circles with their meta-analysis P values (as −log10 values) as a function of genomic position (NCBI Build 36). In each plot, the discovery-stage SNP taken forward to replication stage is represented by a purple diamond (defining a global meta-analysis P value). Local LD structure is reflected by the plotted estimated recombination rates (taken from HapMap) in the region around the associated SNPs and their correlated proxies. The correlations of the lead SNP to other SNPs at the locus are shown on a color scale from r²<0.2 dark blue; 0.2=<r²<0.4 light-blue; 0.4=<r²<0.6 green; 0.6=<r²<0.8 orange; r²>=0.8 red. Superimposed on the plot are the recombination rates (light blue line, second y axis). Gene annotations are shown as the dark blue arrows. The regional plots were drawn using the LocusZoom software. 1a Regional plot of locus 12q24.31 1b Regional plot of locus 12q15 1c Regional association plot of locus 17q21.1; downstream of the lead signal, rs9915547 is indicated (r² 0.22 HapMap CEU with rs11655470), which showed a genome wide significant association with adult intra cranial volume (P=1.5×10⁻¹²) as described in Ikram et al.

Figure 1

Directly genotyped and imputed SNPs are plotted using filled circles with their meta-analysis P values (as −log10 values) as a function of genomic position (NCBI Build 36). In each plot, the discovery-stage SNP taken forward to replication stage is represented by a purple diamond (defining a global meta-analysis P value). Local LD structure is reflected by the plotted estimated recombination rates (taken from HapMap) in the region around the associated SNPs and their correlated proxies. The correlations of the lead SNP to other SNPs at the locus are shown on a color scale from r²<0.2 dark blue; 0.2=<r²<0.4 light-blue; 0.4=<r²<0.6 green; 0.6=<r²<0.8 orange; r²>=0.8 red. Superimposed on the plot are the recombination rates (light blue line, second y axis). Gene annotations are shown as the dark blue arrows. The regional plots were drawn using the LocusZoom software. 1a Regional plot of locus 12q24.31 1b Regional plot of locus 12q15 1c Regional association plot of locus 17q21.1; downstream of the lead signal, rs9915547 is indicated (r² 0.22 HapMap CEU with rs11655470), which showed a genome wide significant association with adult intra cranial volume (P=1.5×10⁻¹²) as described in Ikram et al.

Figure 1

Directly genotyped and imputed SNPs are plotted using filled circles with their meta-analysis P values (as −log10 values) as a function of genomic position (NCBI Build 36). In each plot, the discovery-stage SNP taken forward to replication stage is represented by a purple diamond (defining a global meta-analysis P value). Local LD structure is reflected by the plotted estimated recombination rates (taken from HapMap) in the region around the associated SNPs and their correlated proxies. The correlations of the lead SNP to other SNPs at the locus are shown on a color scale from r²<0.2 dark blue; 0.2=<r²<0.4 light-blue; 0.4=<r²<0.6 green; 0.6=<r²<0.8 orange; r²>=0.8 red. Superimposed on the plot are the recombination rates (light blue line, second y axis). Gene annotations are shown as the dark blue arrows. The regional plots were drawn using the LocusZoom software. 1a Regional plot of locus 12q24.31 1b Regional plot of locus 12q15 1c Regional association plot of locus 17q21.1; downstream of the lead signal, rs9915547 is indicated (r² 0.22 HapMap CEU with rs11655470), which showed a genome wide significant association with adult intra cranial volume (P=1.5×10⁻¹²) as described in Ikram et al.