Genetic architectures of the human hippocampus and those involved in neuropsychiatric traits

Abstract

Background: The hippocampus, with its complex subfields, is linked to numerous neuropsychiatric traits. While most research has focused on its global structure or a few specific subfields, a comprehensive analysis of hippocampal substructures and their genetic correlations across a wide range of neuropsychiatric traits remains underexplored. Given the hippocampus's high heritability, considering hippocampal and subfield volumes (HASV) as endophenotypes for neuropsychiatric conditions is essential.

Methods: We analyzed MRI-derived volumetric data of hippocampal and subfield structures from 41,525 UK Biobank participants. Genome-wide association studies (GWAS) on 24 HASV traits were conducted, followed by genetic correlation, overlap, and Mendelian randomization (MR) analyses with 10 common neuropsychiatric traits. Polygenic risk scores (PRS) based on HASV traits were also evaluated for predicting these traits.

Results: Our analysis identified 352 independent genetic variants surpassing a significance threshold of 2.1 × 10^-9 within the 24 HASV traits, located across 93 chromosomal regions. Notably, the regions 12q14.3, 17q21.31, 12q24.22, 6q21, 9q33.1, 6q25.1, and 2q24.2 were found to influence multiple HASVs. Gene set analysis revealed enrichment of neural differentiation and signaling pathways, as well as protein binding and degradation. Of 240 HASV-neuropsychiatric trait pairs, 75 demonstrated significant genetic correlations (P < 0.05/240), revealing 433 pleiotropic loci. Particularly, genes like ACBD4, ARHGAP27, KANSL1, MAPT, ARL17A, and ARL17B were involved in over 50 HASV-neuropsychiatric pairs. Leveraging Mendelian randomization analysis, we further confirmed that atrophy in the left hippocampus, right hippocampus, right hippocampal body, and right CA1-3 region were associated with an increased risk of developing Parkinson's disease (PD). Furthermore, PRS for all four HASVs were significantly linked to a higher risk of Parkinson's disease (PD), with the highest hazard ratio (HR) of 1.30 (95% CI 1.18-1.43, P = 6.15 × 10⁻⁸) for right hippocampal volume.

Conclusions: These findings highlight the extensive distribution of pleiotropic genetic determinants between HASVs and neuropsychiatric traits. Moreover, they suggest a significant potential for effectively managing and intervening in these diseases during their early stages.

Keywords: Hippocampus; Neuropsychiatric; Parkinson’s disease; Pleiotropic.

Fig. 1

Study overview and workflow.A Schematic illustration of the hippocampus regions. B Sample selection flowchart. C A brief description of the overall workflow and major analyses

Fig. 2

Genomic loci associated with 24 hippocampal and subfield volumes (HASVs). A Ideogram of 93 genomic regions associated with 24 hippocampal and subfield volumes. Orange name labels denote genomic regions that have been widely reported to be associated with hippocampal volume, while red represents newly identified loci in this study. B–G These regional plots illustrate an instance of corresponding loci that exerted influence on multiple HASV traits

Fig. 3

Annotation of risk variants and genes. A The minimum chromatin state across 127 tissue and cell types for candidate SNPs for each of the 24 HASV traits, with lower states indicating higher accessibility and states 1–7 referring to open chromatin states. B The bar charts represent the proportions of RegulomeDB scores 1 or 2 among the risk variants for each of the 24 HASV traits. A lower score suggests a higher likelihood of having a regulatory function. C Histone modifications and transcription factor (TF) peaks were primarily sourced from hippocampus samples provided by ENCODE. When hippocampus-specific data was unavailable, brain data was used instead. The enrichment of candidate SNPs in these epigenomic marks was assessed relative to control variants, which were generated in a 1:1 ratio using vSampler. Statistical significance was determined using a Fisher test. An asterisk denotes statistically significant differences (*P < 0.05; **P < 2.08 × 10⁻⁴, Bonferroni corrected). D The stacked bar charts depict the number of genes mapped using four distinct strategies: physical position, eQTL association, transcriptome-wide association study (TWAS), and multi-marker analysis of genomic annotation (MAGMA), for each of the 24 HASV traits. E Pathway analysis of genes associated with each of the 24 HASV traits based on the molecular signatures database. F Tissue expression results across 29 specific tissue types from GTEx v8 in FUMA. The chromatin states are 1 = active transcription start site (TSS); 2 = flanking active TSS; 3 = transcription at gene 5’ and 3’; 4 = strong transcription; 5 = weak transcription; 6 = genic enhancers; 7 = enhancers; 8 = zinc finger genes and repeats; 9 = heterochromatic; 10 = bivalent/poised TSS; 11 = flanking bivalent/poised TSS/Enh; 12 = bivalent enhancer; 13 = repressed PolyComb; 14 = weak repressed PolyComb; 15 = quiescent/low

Fig. 4

SNP heritability and genetic correlations of 24 HASV traits. A SNP heritability of 24 HASV traits. B Genetic correlations between 24 HASV traits. One asterisk denotes the nominal level (0.05), while two asterisks indicate genetic correlations that have survived multiple testing adjustments using the Bonferroni correction (P < 0.05/276). The colors represent the magnitude of genetic correlations

Fig. 5

Genetic connections between 24 HASV traits and 10 brain disorders.A Genetic correlations between 24 HASV traits (X-axis) and 10 brain disorders (Y-axis). Genetic correlation was estimated using the LDSC method. Asterisk denotes statistically significant differences, *P < 0.05; **P < 2.08 × 10⁻⁴ (0.05/240, Bonferroni corrected). B Genetic overlaps between 24 HASV traits (X-axis) and 10 brain disorders (Y-axis). Genetic overlap was estimated using the GPA method. We introduced PAR as PM 11/(PM10 + PM01 + PM11) to represent the proportion of pleiotropic SNPs associated with both traits against the proportion of SNPs associated with at least 1 trait. Asterisk denotes statistically significant differences, *P < 0.05; **P < 2.08 × 10⁻⁴ (0.05/240, Bonferroni corrected). LDSC, linkage disequilibrium score regression; GPA, genetic analysis incorporating pleiotropy and annotation method; PAR, pleiotropy association ratio; PM11, proportion of genetic variants associated with both traits; AD, Alzheimer’s disease; ADHD, attention-deficit hyperactivity disorder; AN, anorexia nervosa; ANX, anxiety disorder; BIP, bipolar disorder; PD, Parkinson’s disease; PTSD, post-traumatic stress disorder; SCZ, schizophrenia

Fig. 6

Causal effects between HASV traits and brain disorders using Mendelian Randomization. A This heatmap presents the results of two-sample Mendelian randomization (MR) analyses for the 75 trait pairs (direction is HASV to brain disorders) using the IVW method. Statistically significant differences are denoted by asterisks: *P < 0.05; **P < 6.67 × 10⁻⁴ (0.05/75, Bonferroni corrected). B Forest plots for the four HASV traits that were Bonferroni corrected significant, showing causal effects on PD using two MR methods: IVW and CAUSE. IVW inverse variance weighted, CAUSE causal analysis using summary effect estimates, OR odds ratio, AD Alzheimer’s disease, ADHD attention-deficit hyperactivity disorder, AN anorexia nervosa, ANX anxiety disorder, BIP bipolar disorder, PD Parkinson’s disease, PTSD post-traumatic stress disorder, SCZ schizophrenia

Fig. 7

Cumulative incidence of Parkinson's disease stratified by PRS. A–D These survival curves include 441,731 individuals who had not undergone brain MRI scans and had no prior diagnosis of Parkinson’s disease at the time of enrollment. The y-axis represents the cumulative incidence (1 minus the Kaplan–Meier survival estimate) of a Parkinson’s disease diagnosis, while the x-axis indicates the number of years since enrollment in the UK Biobank. Individuals with a high polygenic score are depicted in red, those in the intermediate tertiles are in orange, and those in the low tertiles are in green. The 95% confidence intervals, derived from the cumulative hazard standard error, are represented with lighter shades