Séminaire de Clara Moreau

Vendredi 21 octobre à 14h30, Salle Henri Gastaut INT

Impact of genetic heterogeneity and pleiotropy in psychiatry on brain functional connectivity

Clara Moreau (Human Genetics and Cognitive Functions, CNRS UMR 3571, Université de Paris, Institut Pasteur)

(invitée par Guillaume Auzias)

Abstract:

Genetic heterogeneity and pleiotropy shape brain connectivity in psychiatric conditions. Polygenicity (multiple genetic variants associated with one condition) and pleiotropy (one genetic variant influencing more than one trait) are key properties of the genomic architecture of psychiatric conditions and represent major challenges in identifying mechanisms. We processed nine resting-state fMRI datasets including 32,726 individuals, to examine the connectome-wide effects of 15 copy number variants, 7 polygenic scores (common variants), and 4 idiopathic psychiatric conditions (Autism, Schizophrenia, ADHD, Bipolar disorder). Pleiotropy, measured by genetic and transcriptomic correlations across pairs of conditions/traits, showed significant concordance with connectomic correlations between the same pairs of conditions/traits. This suggests a causal genetic component for shared connectivity. We also found that effect sizes of CNVs on FC were correlated with their effects on cognitive ability. However, their effect sizes adjusted for the number of genes decreased from small oligogenic to large multigenic CNVs. Polygenic scores had disproportionately low effects on FC. Finally, multivariate analyses of genetic risks and psychiatric conditions showed convergence on the overconnectivity of the thalamus with the somatomotor network. This is in line with the fact that gross and fine motor skills are widely impaired in patients referred to NDD clinics. Our findings open avenues to delineate general mechanisms – amenable to intervention – in psychiatric conditions.