Genetic Influences on the Developing Young Brain and Risk for Neuropsychiatric Disorders

Alex, Ann Mary; Buß, Claudia; Davis, Elysia Poggi; Campos, Gustavo de los; Donald, Kirsten A.; Fair, Damien A.; Gaab, Nadine; Gao, Wei; Gilmore, John H.; Girault, Jessica B.; Grewen, Karen; Groenewold, Nynke A.; Hankin, Benjamin L.; Ipser, Jonathan; Kapoor, Shreya; Kim, Pilyoung; Lin, Weili; Luo, Shan; Norton, Elizabeth S.; O’Connor, Thomas; Piven, Joseph; Qiu, Anqi; Rasmussen, Jerod; Skeide, Michael; Stein, Dan J.; Styner, Martin; Thompson, Paul M.; Wakschlag, Laurie; Knickmeyer, Rebecca

doi:10.1016/j.biopsych.2023.01.013

Cited by 13 publications

(7 citation statements)

References 116 publications

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“…This strong relationship between genetics, sex differentiation, and the PFC in the prenatal and neonatal brain, implies a genetic basis for our data-driven results and its importance in brain-behavior relationships. Future work should consider gene-environmental interactions [108].…”

Section: Discussionmentioning

confidence: 99%

Sex differences in brain-behavior relationships in the first two years of life

Fenske,

Liu,

Chen

et al. 2024

Preprint

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Background: Evidence for sex differences in cognition in childhood is established, but less is known about the underlying neural mechanisms for these differences. Recent findings suggest the existence of brain-behavior relationship heterogeneities during infancy; however, it remains unclear whether sex underlies these heterogeneities during this critical period when sex-related behavioral differences arise. Methods: A sample of 316 infants was included with resting-state functional magnetic resonance imaging scans at neonate (3 weeks), 1, and 2 years of age. We used multiple linear regression to test interactions between sex and resting-state functional connectivity on behavioral scores of working memory, inhibitory self-control, intelligence, and anxiety collected at 4 years of age. Results: We found six age-specific, intra-hemispheric connections showing significant and robust sex differences in functional connectivity-behavior relationships. All connections are either with the prefrontal cortex or the temporal pole, which has direct anatomical pathways to the prefrontal cortex. Sex differences in functional connectivity only emerge when associated with behavior, and not in functional connectivity alone. Furthermore, at neonate and 2 years of age, these age-specific connections displayed greater connectivity in males and lower connectivity in females in association with better behavioral scores. Conclusions: Taken together, we critically capture robust and conserved brain mechanisms that are distinct to sex and are defined by their relationship to behavioral outcomes. Our results establish brain-behavior mechanisms as an important feature in the search for sex differences during development.

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Section: Discussionmentioning

confidence: 99%

Sex differences in brain-behavior relationships in the first two years of life

Fenske,

Liu,

Chen

et al. 2024

Preprint

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“…Second, the absence of genetic analysis in the current study might overlook the interplay between genetic factors and early life exposures on neurodevelopment. Genetic variations help shape individual differences in functional 54–56 and structural connectivity 57–59 . These variations further interact with the environmental effects (i.e., epigenetics/maternal) 60–62 .…”

Section: Discussionmentioning

confidence: 99%

Brain age prediction and deviations from normative trajectories in the neonatal connectome

Sun,

Mehta,

Khaitova

et al. 2024

Preprint

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Structural and functional connectomes undergo rapid changes during the third trimester and the first month of postnatal life. Despite progress, our understanding of the developmental trajectories of the connectome in the perinatal period remains incomplete. Brain age prediction uses machine learning to estimate the brain's maturity relative to normative data. The difference between the individual's predicted and chronological age, or brain age gap (BAG),represents the deviation from these normative trajectories. Here, we assess brain age prediction and BAGs using structural and functional connectomes for infants in the first month of life. We used resting-state fMRI and DTI data from 611 infants (174 preterm; 437 term) from the Developing Human Connectome Project (dHCP) and connectome-based predictive modeling to predict postmenstrual age (PMA). Structural and functional connectomes accurately predicted PMA for term and preterm infants. Predicted ages from each modality were correlated. At the network level, nearly all canonical brain networks, even putatively later developing ones, generated accurate PMA prediction. Additionally, BAGs were associated with perinatal exposures and toddler behavioral outcomes. Overall, our results underscore the importance of normative modeling and deviations from these models during the perinatal period.

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“…Thus, further contributing to accelerated experience of emotional and behavioral difficulties, as identified in this study. Furthermore, neurobiological differences have been found to be associated with genetic risk for mood disorders and related traits (Alex et al, 2023; Shen et al, 2020; Fernandez-Cabello et al, 2022; Alnæs et al, 2019; Cheng et al, 2022; Patel et al, 2021), indicating potential for a neurodevelopmental component directly or indirectly contributing to higher and increasing emotional and behavioral difficulties, as well as risk of disorder.…”

Section: Discussionmentioning

confidence: 99%

Childhood trajectories of emotional and behavioral difficulties are related to polygenic liability for mood and anxiety disorders

Bakken,

Parker,

Hannigan

et al. 2023

Preprint

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BackgroundSymptoms related to mood and anxiety disorders often present in childhood and adolescence. Some of the genetic liability for mental disorders, and emotional and behavioral difficulties seems to be shared. Yet, it is unclear how genetic liability for mood and anxiety disorders influence trajectories of childhood emotional and behavioral difficulties, and if specific developmental patterns associate with higher genetic liability for these disorders.MethodsThis study uses data from a genotyped sample of children (n= 54,839) from the Norwegian Mother, Father and Child Cohort Study (MoBa). We use latent growth models (1.5-5 years) and latent profile analyses (1.5-8 years) to quantify childhood trajectories and profiles of emotional and behavioral difficulties and diagnoses. We examine associations between these trajectories and profiles with polygenic scores for bipolar disorder (PGSBD), anxiety (PGSANX), depression (PGSDEP), and neuroticism (PGSNEUR).ResultsAssociations between PGSDEP, PGSANXand PGSNEUR, and emotional and behavioral difficulties in childhood were developmentally stable rather than age specific. Higher PGSANXand PGSDEPwere associated with steeper increases in behavioral difficulties across early childhood. Latent profile analyses identified five profiles. All PGS were associated with probability of classification into profiles characterized by some form of difficulties (vs. a normative reference profile), but only PGSBDwas uniquely associated with a single developmental profile.ConclusionsOur findings indicate that genetic risk for mood disorders and related traits contribute to a more rapidly increasing and higher overall burden of emotional and behavioral difficulties across early and middle childhood, with some indications for disorder-specific profiles. These findings of associations between childhood trajectories and symptom profiles and genetic and clinical susceptibility for mental disorders, may form the basis for more targeted early interventions.

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Genetic Influences on the Developing Young Brain and Risk for Neuropsychiatric Disorders

Cited by 13 publications

References 116 publications

Sex differences in brain-behavior relationships in the first two years of life

Sex differences in brain-behavior relationships in the first two years of life

Brain age prediction and deviations from normative trajectories in the neonatal connectome

Childhood trajectories of emotional and behavioral difficulties are related to polygenic liability for mood and anxiety disorders

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