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 (rg¼ 0.155). Our findings suggest novel biological pathways
through which human genetic variation influences hippocampal volume and risk for
neuropsychiatric illness.
