Where the genome meets the connectome: understanding how genes shape human brain connectivity

Abstract

The integration of modern neuroimaging methods with genetically informative designs and data can shed light on the molecular mechanisms underlying the structural and functional organisation of the human connectome. Here, we review studies that have investigated the genetic basis of human brain network structure and function through three complementary frameworks: (1) the quantification of phenotypic heritability through classical twin designs; (2) the identification of specific DNA variants linked to phenotypic variation through association and related studies; and (3) the analysis of correlations between spatial variations in imaging phenotypes and gene expression profiles through the integration of neuroimaging and transcriptional atlas data. We consider the basic foundations, strengths, limitations, and discoveries associated with each approach. We present converging evidence to indicate that anatomical connectivity is under stronger genetic influence than functional connectivity and that genetic influences are not uniformly distributed throughout the brain, with phenotypic variation in certain regions and connections being under stronger genetic control than others. We also consider how the combination of imaging and genetics can be used to understand the ways in which genes may drive brain dysfunction in different clinical disorders.

Longer screen time utilization is associated with the polygenic risk for Attention-deficit/hyperactivity disorder with mediation by brain white matter microstructure

“…Firstly, we focused on the white matter microstructure in this study because anatomical measures are reported to be more closely related to genetic factors than functional connectivity. 84 At the time of the writing of this paper, there is no clear meta-analytic evidence of common functional alterations across individuals with ADHD. 85 , 86 In the future, other types of imaging data like functional MRI may be considered.…”

Sexually divergent development of depression-related brain networks during healthy human adolescence

“…Limitations of the study include our reliance on gene expression maps from postmortem examination of six adult, mostly male, brains. This dataset is used widely and has been invaluable in shedding new light on the molecular correlates of neuroimaging phenotypes ( 77 ). Biological validation of sexually divergent adolescent development of this cortico-subcortical system derived from fMRI would be more directly informed by sex-specific human brain maps of whole-genome transcription in adolescence, but to the best of our knowledge, these data are not currently available.…”

Genetic overlap between multivariate measures of human functional brain connectivity and psychiatric disorders

“…While both neuroimaging and genetic studies each have pointed to synaptic alterations in psychiatric disorders, only a few have specifically tested this hypothesis in an integrated imaging-genetics framework. A few studies have explored the genetic architecture of functional brain connectivity 19–23 , and studies assessing polygenic risk scores have indicated links between psychiatric disorders and abnormal brain connectivity 24,25 . Previous studies also illustrated genetic correlation between various brain imaging phenotypes and psychiatric disorders that confirm a large degree of shared effect sizes across single nucleotide polymorphisms (SNPs) 26–28 .…”

“…A few studies have explored the genetic architecture of functional brain connectivity [19][20][21][22][23] , and studies assessing polygenic risk scores have indicated links between psychiatric disorders and abnormal brain connectivity 24,25 . Previous studies also illustrated genetic correlation between various brain imaging phenotypes and psychiatric disorders that confirm a large degree of shared effect sizes across single nucleotide polymorphisms (SNPs) [26][27][28] .…”