The genetic landscape of human functional brain connectivity.

Maciel, Bernardo de Apc; Schipper, Marijn; Romero, Cato; de Leeuw, Christiaan; Helwegen, Koen; Posthuma, Danielle; Savage, Jeanne E; van den Heuvel, Martijn P · Nat Commun · 2026

cross_sectional · Level IV

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Abstract

Investigating the genetic underpinnings of functional brain connectivity is essential to understand how genetic variation influences brain health and disease. Here, a mass-univariate approach was adopted to study the genetic architecture of functional brain circuitry (N<sub>total</sub> = 28,159 subjects) with high spatial resolution (82 brain regions). Common genetic variants explained individual differences in 33% of all 3321 inter-regional functional pathways with 72 significant associations reflecting widespread, pleiotropic effects across the connectome. These associations were mapped to five genes-PAX8, EphA3, SLC39A12, THBS1 and APOE-with known associations with brain phenotypes and which converged in biological processes related to neurodevelopment and cardiovascular and cognitive traits (enrichment minimum p = 3.0 × 10<sup>-6</sup> and p = 1.6 × 10<sup>-5</sup>, respectively). Our findings show that the genetic component of individual differences in functional brain connectivity is largely shared throughout the brain, highlighting the importance of genetic variation in large-scale brain organisation and its relationship with cognitive function and overall health.

Medical subject headings