Genome wide association study of incomplete hippocampal inversion in adolescents

PLoS One. 2020 Jan 28;15(1):e0227355. doi: 10.1371/journal.pone.0227355. eCollection 2020.


Incomplete hippocampal inversion (IHI), also called hippocampal malrotation, is an atypical presentation of the hippocampus present 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 cohort obtained from the IMAGEN database. The incidence rate of IHI was 26.1%. Loci with P<1e-5 were followed up in a validation cohort comprising 161 subjects from the PING study. Summary statistics from the discovery cohort were used to compute IHI heritability as well as genetic correlations with other traits. A locus 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 locus implicated genes AQP4 and KCTD1. However, neither this 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 reached nominal P< = 0.013.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Aquaporin 4 / genetics
  • Brain Diseases / diagnostic imaging
  • Brain Diseases / genetics*
  • Brain Diseases / physiopathology
  • Co-Repressor Proteins / genetics
  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study*
  • Hippocampus / diagnostic imaging
  • Hippocampus / physiopathology*
  • Humans
  • Male
  • Polymorphism, Single Nucleotide / genetics
  • Temporal Lobe / physiopathology


  • AQP4 protein, human
  • Aquaporin 4
  • Co-Repressor Proteins
  • KCTD1 protein, human