Incomplete hippocampal inversion (IHI) is an anatomical brain pattern found in about 20% of the population and may be associated with an increased risk of epilepsy and schizophrenia. Previous attempts at elucidating the genetic underpinnings of IHI and its links with disorders have been limited by sample size. We applied a deep-learning based automatic rating method for IHI to conduct a genome-wide association study (GWAS) on 39,432 European UK Biobank participants. Automatic rating indicated an IHI prevalence of 16% in the left hemisphere and 3% in the right. We performed GWAS using a mixed model with a Leave One Chromosome Out approach. We identified six novel loci with six lead variants associated with IHI in the left hemisphere and five loci with seven lead variants in the right hemisphere, three variants of which replicated in an independent sample for left and right IHI each. Functional annotation using gene-based tests such as mBAT-combo, h-MAGMA, summary-data-based Mendelian randomization (multi-SMR) or known expression quantitative trail loci (eQTLs) led to the discovery of genes implicated among others in the pathogenesis of Alzheimer's disease, in schizophrenia, bipolar disorder and temporal lobe epilepsy (DAAM1, GPR135, CREB3L4, SLC39A1, SLIT2, LEKR1, CCDC50, IL1RAP and GMNC). By investigating gene expression over time, we identified several genes with differential expression during the pre-natal development of the hippocampus (DAAM1 and CCDC50). We reported heritability using twin studies (H 2 lef t = 0.34 (se = 0.05); H 2 right = 0.37 (se = 0.05)) as well as variant heritability (h 2 lef t = 0.24 (se = 0.014); h 2 right = 0.20(se = 0.014)). The genetic correlation between IHI and bipolar disorder (BIP) was nominally significant, and we did not observe a significant association with epilepsy and schizophrenia. Our results give a first glimpse into the genetic underpinnings of IHI. and combined sample of discovery and replication cohort will be made available in the GWAS catalog.
Hemforth et al. (Thu,) studied this question.