Genome wide association study of incomplete hippocampal inversion in adolescents

Abstract : Incomplete hippocampal inversion (IHI), also called hippocampal malrotation,is an atypical presentation of the hippocampuspresent in about 20% of healthy individuals. Here we conducted the first genome-wide association study (GWAS) in IHI to elucidate the genetic underpinnings that may contribute to the incomplete inversion during brain development.A total of 1381 subjects contributed to the discovery cohortobtained from the IMAGEN database. The incidence rate of IHI was 26.1%. Loci with P<1e-5were followed up in a validation cohort comprising 161subjects from the PING study.Summary statistics from the discovery cohort were used to compute IHI heritability as well as genetic correlations with other traits.Alocus on 18q11.2 (rs9952569; OR=1.999; Z=5.502; P=3.755e-8) showed a significant association with the presence of IHI. A functional annotation of the locusimplicatedgenes AQP4and KCTD1. However, neitherthis locus nor the other 16 suggestive loci reached a significant p-value in the validation cohort. The h2 estimate was 0.54 (sd: 0.30) and was significant (Z=1.8; P=0.036). The top three genetic correlations of IHI were with traits representing either intelligence or education attainment and reachednominal P<=0.013.