Novel genetic loci associated with hippocampal volume

Abstract

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r_g=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

Figure 1. Common genetic variants associated with hippocampal volume (N=26,814 of European ancestry).

A Manhattan plot displays the association P value for each single-nucleotide polymorphism (SNP) in the genome (displayed as –log₁₀ of the P-value). Genome-wide significance is shown for the P=5 × 10⁻⁸ threshold (solid line) and also for the suggestive significance threshold of P=1 × 10⁻⁶ (dotted line). The most significant SNP within an associated locus is labeled. For the significant loci and age-dependent loci (Chromosome 19) we labeled the nearest gene, which is not necessarily the gene of action.

Figure 2. Functional annotation within genome-wide significant loci.

For each panel (a–f), zoomed-in Manhattan plots (±400 kb from top SNP) are shown with gene models below (GENCODE version 19). Plots below are zoomed to highlight the genomic region that likely harbors the causal variant(s) (r²>0.8 from the top SNP). Genomic annotations from the Roadmap Epigenomics Consortium are displayed to indicate potential functionality (see Methods for detailed track information). Each plot was made using the LocusTrack software (see URLs).

Figure 3. Analysis of variance explained, functional annotation, and pathway analysis.

LDSCORE regression analysis for different functional annotation categories (described further in Finucane et al.26). Plotted values are the proportion of h²_g explained divided by the proportion of SNPs in a given functional category. Values are significantly over- or under-represented if they differ significantly from 1. Values are plotted with a standard error calculated with a jackknife in LDSCORE. Evolutionarily conserved regions across mammals significantly contributed to the heritability of hippocampal volume (indicated by **).