Genetic architecture of the structural connectome

Abstract

Myelinated axons form long-range connections that enable rapid communication between distant brain regions, but how genetics governs the strength and organization of these connections remains unclear. We perform genome-wide association studies of 206 structural connectivity measures derived from diffusion magnetic resonance imaging tractography of 26,333 UK Biobank participants, each representing the density of myelinated connections within or between a pair of cortical networks, subcortical structures or cortical hemispheres. We identify 30 independent genome-wide significant variants after Bonferroni correction for the number of measures studied (126 variants at nominal genome-wide significance) implicating genes involved in myelination (SEMA3A), neurite elongation and guidance (NUAK1, STRN, DPYSL2, EPHA3, SEMA3A, HGF, SHTN1), neural cell proliferation and differentiation (GMNC, CELF4, HGF), neuronal migration (CCDC88C), cytoskeletal organization (CTTNBP2, MAPT, DAAM1, MYO16, PLEC), and brain metal transport (SLC39A8). These variants have four broad patterns of spatial association with structural connectivity: some have disproportionately strong associations with corticothalamic connectivity, interhemispheric connectivity, or both, while others are more spatially diffuse. Structural connectivity measures are highly polygenic, with a median of 9.1 percent of common variants estimated to have non-zero effects on each measure, and exhibited signatures of negative selection. Structural connectivity measures have significant genetic correlations with a variety of neuropsychiatric and cognitive traits, indicating that connectivity-altering variants tend to influence brain health and cognitive function. Heritability is enriched in regions with increased chromatin accessibility in adult oligodendrocytes (as well as microglia, inhibitory neurons and astrocytes) and multiple fetal cell types, suggesting that genetic control of structural connectivity is partially mediated by effects on myelination and early brain development. Our results indicate pervasive, pleiotropic, and spatially structured genetic control of white-matter structural connectivity via diverse neurodevelopmental pathways, and support the relevance of this genetic control to healthy brain function.

Fig. 1. Study overview.

Top left: Measurement of tractograms from participants with brain imaging data in the UK Biobank. Top middle: genomic locations of common genetic variants associated with structural connectivity, with chromosomes in ascending order (first row: chr1-8; second row: chr9-16; third row: chr17-22 and chrX). 30 independent variants were genome-wide significant after Bonferroni correction for the 206 structural connectivity measures studied (dark blue), and 96 more reached nominal genome-wide significance (light blue). Top right: the 30 variants cluster into four broad patterns of spatial association: corticothalamic and interhemispheric (3 variants), corticothalamic only (1 variant), interhemispheric only (8 variants), and spatially diffuse (18 variants). Heatmaps denote the median effect size magnitude (|β | ) of variants with each pattern on each of the 206 structural connectivity measures. Bottom left: heritability (h²), polygenicity (π), and selection parameter (S) for each of the 206 measures. Bottom middle and right: heritability enrichments for regions with increased chromatin accessibility in each of 6 adult brain cell types, and genetic correlations with 15 brain-related traits. Bars show maximums across the 206 measures; red/blue bars are significant after Bonferroni correction. OPC oligodendrocyte progenitor cell, ADHD attention-deficit/hyperactivity disorder, ALS amyotrophic lateral sclerosis, disord. disorder. Error bars represent 95% confidence intervals.

Fig. 2. Tractography across 26,333 UK Biobank participants.

A Participant-averaged connectivity between each pair of parcels in the 200-parcel Schaefer cortical atlas + 14 subcortical parcels from the Harvard-Oxford atlas (in order: left thalamus, left caudate, left putamen, left pallidum, left hippocampus, left amygdala, left accumbens, right thalamus, right caudate, right putamen, right pallidum, right hippocampus, right amygdala, right accumbens). Heatmap entries indicate the weighted number of streamlines connecting each pair of parcels, averaged across participants (see “Tractography pipeline”, “Methods”). Color bands along the top and left indicate Yeo 7 networks. LH left-hemisphere, RH right-hemisphere, Vis visual, SomMot somatomotor, DorsAttn dorsal attention, SalVentAttn salience/ventral attention, Limbic limbic, Cont control, Default default mode. B Participant averages of the 206 connectivity measures. The three large tiles above the diagonal represent hemisphere-level measures. C Inter-replicate type 3 intraclass correlation coefficients (ICCs) across 2400 participants with replicate MRI scans, calculated using the intraclass_corr function from the pingouin Python package.

Fig. 3. Manhattan plot of each variant’s minimum p value across the 206 structural connectivity measures.

Gold variants indicate linkage disequilibrium (LD) clumps passing nominal genome-wide significance (dashed black line); black diamonds highlight the lead variant in each clump. Nearest genes are labeled for each clump passing Bonferroni-corrected genome-wide significance (solid black line).

Fig. 4. Spatial patterns of association with structural connectivity.

For brevity, only the 12 most significant lead variants are shown; the remaining 18 are shown in Supplementary Fig. 1. Asterisks (*) indicate associations passing Bonferroni-corrected genome-wide significance (p < 5 × 10^–8 / 206 ≈ 2.4 × 10⁻¹⁰), while dots (·) indicate associations significant after Bonferroni correction for just the 30 variants times the number of measures (p < 0.05 / 30 / 206 ≈ 8.1 × 10^–6). Effect sizes (β) are oriented with respect to the minor allele, so positive effect sizes (red) indicate that the minor allele is associated with increased structural connectivity, while negative effect sizes (blue) indicate that the minor allele is associated with decreased connectivity. LH left-hemisphere, RH right-hemisphere, Vis visual, SomMot somatomotor, DorsAttn dorsal attention, SalVentAttn salience/ventral attention, Limbic limbic, Cont control, Default default mode.

Fig. 5. Global properties of the genetic architecture of structural connectivity.

LH left-hemisphere, RH right-hemisphere, Vis visual, SomMot somatomotor, DorsAttn dorsal attention, SalVentAttn salience/ventral attention, Limbic limbic, Cont control, Default default mode.