Abstract
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.
Highlights
Human hippocampi are small structures, one in each temporal lobe that belongs to the brain’s limbic system and is known to be mainly involved in memory processes such as long term memorisation and spatial navigation [1]
The second cohort was obtained from the Pediatric Imaging Neurocognition and Genetics (PING) Study database
SNPs in the discovery cohort (IMAGEN) with p
Summary
Human hippocampi are small structures, one in each temporal lobe that belongs to the brain’s limbic system and is known to be mainly involved in memory processes such as long term memorisation and spatial navigation [1]. There is a variation to the typical presentation of the hippocampi in normal subjects: the incomplete hippocampal inversion (IHI) referred to as hippocampal malrotation (Fig 1). This anatomical variant has been initially observed in healthy subjects by [11] and mostly observed in patients with epilepsy [12,13]. It has been suggested that IHI might interfere with the quality of hippocampal segmentation for volumetric analysis [16,18], which may be clinically relevant, since the hippocampal volume can predict the response to antidepressant in patients without IHI [4,5]
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