Unraveling the Genetic Tapestry of Early Human Brain Development: Insights from Imaging Genetics

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Imaging genetics has been a powerful tool in unraveling the intricate interplay between genetics and brain structure or function. While the majority of research in this field has historically focused on the adolescent and adult human brain, recent strides have been made to extend these investigations into the critical period of embryonic life through early childhood.

This shift in focus is pivotal, as disruptions in gene expression during this developmental window can result in lifelong changes in brain morphology and function. Even common genetic variations may exert their influence on early neurodevelopmental processes, potentially elevating the risk for psychiatric conditions in later life.

This paper provides an in-depth review of empirical evidence supporting this hypothesis, with a particular emphasis on magnetic resonance imaging (MRI) studies.

Introduction

The human brain undergoes its most dynamic phase of development from embryonic life through early childhood. This crucial period lays the foundation for a lifetime of cognitive, emotional, and behavioral patterns. Disrupted gene expression during these formative years can have profound and lasting effects on brain structure and function, increasing susceptibility to psychiatric conditions later in life. The utilization of neuroimaging techniques during early life opens up unprecedented opportunities for identifying at-risk populations in infancy, facilitating primary prevention, and developing interventions to modify adverse trajectories.

Heritability of Brain Imaging Phenotypes in Early Life

This section delves into the heritability of brain imaging phenotypes during early development. Highlighting studies that employ magnetic resonance imaging, the review explores the genetic underpinnings of structural and functional variations in the developing brain.

Candidate Gene Studies: Exploring Brain Structure, Function, and Connectivity

The next segment focuses on candidate gene studies that elucidate the relationship between specific genes and various aspects of brain development. Examining structural morphology, functional activity, and connectivity patterns, these studies contribute to a nuanced understanding of how individual genes influence the developing brain.

Polygenic Scores and Psychiatric Risk Genes

This section explores the intersection between psychiatric risk genes and early-life brain phenotypes through the lens of polygenic scores. By integrating genetic data, researchers aim to identify subtle genetic influences that may contribute to the early emergence of psychiatric vulnerabilities.

Genome-Wide Studies on Early Childhood Brain Imaging Phenotypes

Shifting from candidate gene approaches, this part reviews genome-wide studies that provide a comprehensive view of the genetic landscape influencing various brain imaging phenotypes during early childhood. This expansive approach allows for the identification of novel genetic factors contributing to neurodevelopment.

Origins: Advancing Imaging Genetics in Infancy

The paper introduces ORIGINs, a working group within the ENIGMA consortium (Enhancing NeuroImaging Genetics through Meta-Analysis), designed to facilitate large-scale imaging genetics studies specifically focused on infancy and early childhood. This collaborative effort aims to consolidate data, standardize methodologies, and promote cross-disciplinary research in the pursuit of a deeper understanding of early human brain development.

Heritability

Twin studies have emerged as invaluable tools in unraveling the genetic contributions to early brain phenotypes, shedding light on the heritability of various structural and functional aspects during infancy. At the forefront of these investigations, global white matter volume (WMV) and global gray matter volume (GMV) have exhibited notable heritability at around 1 month of age.

Genetic effects account for approximately 85% of the variance in WMV and 56% in GMV during this early developmental stage (14). Interestingly, head size, a seemingly related trait, displays negligible heritability in infancy, marking a distinct departure from the patterns observed in older children and adults (15).

Intriguingly, global cortical surface area (SA) demonstrates high heritability (78%) during early infancy, while global cortical thickness (CT) exhibits lower heritability (29%) (19). This dynamic changes in adulthood, where both SA and CT emerge as highly heritable traits (89% and 81%, respectively) with distinct genetic factors influencing each measure (20, 21, 22). These findings underscore the complexity of genetic influences on cortical structure, with early infancy characterized by a unique interplay between genetic and environmental factors.

White matter microstructure, a critical component of brain connectivity, also displays moderate heritability during early life. Approximately 30% to 60% of the variability in mean fractional anisotropy (FA) is attributed to genetic factors, along with similar estimates for other diffusivity indices (23, 24). These heritability rates differ significantly from those observed in adults, where estimates for FA range from 72% to 88% (25). Despite substantial variations in heritability across individual tracts, a latent measure of white matter microstructure consolidates a significant proportion of heritable variation in neonates (50%) (26).

The realm of resting-state functional MRI unveils a nuanced picture of genetic effects during the first two years of life. Gao et al. (29) reported modest genetic effects on within-network connectivity in neonates, with specific visual and frontoparietal networks exhibiting above-average effects. As age progresses, the most heritable networks shift, with genetic effects being strongest for the auditory network at age 2 years. However, these effects are notably less robust than those observed in adolescents and adults (30, 31, 32). Between-network connectivity, too, reveals minimal genetic effects in neonates (33).

Intergenerational Transmission and the Wilson Effect

The influence of genetics on imaging phenotypes extends beyond the individual, with studies reporting intergenerational transmission likely influenced by a combination of genetic, epigenetic, and environmental factors (34, 35, 36). Investigations into the transmission from mothers to their 5-year-old children revealed significant effects on sulcal phenotypes in the right frontal and parietal cortices (35).

A recurring theme in these studies is the observation that heritability tends to be higher in adulthood compared to infancy. While seemingly paradoxical, this mirrors patterns observed in IQ, where increasing heritability during development is known as the Wilson effect (37). The Wilson effect is attributed to gene-environment correlations that intensify with age.

In other words, as individuals age, they actively shape their environments in ways that correlate with their genetic predispositions. Alternatively, the higher heritability observed in later ages could be indicative of stronger genetic influences on postnatal processes such as myelination and shifts in white versus gray matter proportions across development.

To disentangle these complex dynamics, large-scale longitudinal studies, such as those initiated by the ENIGMA plasticity working group, are essential. Their exploration of heritability in brain change rates, utilizing five longitudinal twin cohorts, demonstrated higher heritability in adults compared to children (39). This pioneering work marks a significant step toward unraveling the intricate interplay between genes and environmental factors across the lifespan, providing a foundation for understanding the genetic amplification models that may govern neuroimaging phenotypes.

Conclusion

In conclusion, this comprehensive review underscores the importance of extending imaging genetics research to the critical phase of embryonic life through early childhood. By bridging the gap in our understanding of how genes influence early neurodevelopmental processes, we can identify at-risk populations, implement primary prevention strategies, and develop targeted interventions to alter adverse trajectories before they become clinically manifest. The establishment of initiatives like ORIGINs further exemplifies the commitment of the scientific community to advancing our understanding of the genetic tapestry woven during the earliest stages of human brain development.


reference link :https://www.sciencedirect.com/science/article/pii/S0006322323000409#sec3

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