The association of polygenic risk for schizophrenia, bipolar disorder, and depression with neural connectivity in adolescents and young adults: examining developmental and sex differences

Jacquelyn L Meyers ,J Zhang,Gayathri Pandey ,Sivan Kinreich ,Andrey P Anokhin ,Laura Almasy ,Ayman H Fanous ,Emma C Johnson ,Chella Kamarajan ,Martin H Plawecki ,Jessica E Salvatore ,Howard J Edenberg ,Tatiana Foroud ,John I Nürnberger ,Fazil Alıev ,Ashwini K Pandey ,David B Chorlian ,Tim B Bigdeli ,Arpana Agrawal ,Alison Goate ,Bernice Porjesz

doi:10.1038/s41398-020-01185-7

Abstract

Neurodevelopmental abnormalities in neural connectivity have been long implicated in the etiology of schizophrenia (SCZ); however, it remains unclear whether these neural connectivity patterns are associated with genetic risk for SCZ in unaffected individuals (i.e., an absence of clinical features of SCZ or a family history of SCZ). We examine whether polygenic risk scores (PRS) for SCZ are associated with functional neural connectivity in adolescents and young adults without SCZ, whether this association is moderated by sex and age, and if similar associations are observed for genetically related neuropsychiatric PRS. One-thousand four-hundred twenty-six offspring from 913 families, unaffected with SCZ, were drawn from the Collaborative Study of the Genetics of Alcoholism (COGA) prospective cohort (median age at first interview = 15.6 (12–26), 51.6% female, 98.1% European American, 41% with a family history of alcohol dependence). Participants were followed longitudinally with resting-state EEG connectivity (i.e., coherence) assessed every two years. Higher SCZ PRS were associated with elevated theta (3–7 Hz) and alpha (7–12 Hz) EEG coherence. Associations differed by sex and age; the most robust associations were observed between PRS and parietal-occipital, central-parietal, and frontal-parietal alpha coherence among males between ages 15–19 (B: 0.15–0.21, p < 10–4). Significant associations among EEG coherence and Bipolar and Depression PRS were observed, but differed from SCZ PRS in terms of sex, age, and topography. Findings reveal that polygenic risk for SCZ is robustly associated with increased functional neural connectivity among young adults without a SCZ diagnosis. Striking differences were observed between men and women throughout development, mapping onto key periods of risk for the onset of psychotic illness and underlining the critical importance of examining sex differences in associations with neuropsychiatric PRS across development.

Highlights

Schizophrenia (SCZ) is a debilitating neuropsychiatric syndrome with typical onset during the second decade of life, and characterized by pronounced deficits in sensory and cognitive processing[1]
We found that SCZ polygenic risk scores (PRS) were associated with increased
Findings for PRS based on the p < 0.05 threshold withstood a multiple test correction (FDR < 0.010), with the majority of coherence pairs in these frequency bands showing strong association with SCZ PRS

Summary

Introduction

Schizophrenia (SCZ) is a debilitating neuropsychiatric syndrome with typical onset during the second decade of life, and characterized by pronounced deficits in sensory and cognitive processing[1]. Investigating neurodevelopmental patterns of connectivity in unaffected adolescents and young adults, at varying levels of polygenic susceptibility, may uncover basic patterns of brain connectivity that could underlie development of the disorder This information can elucidate basic neurobiological mechanisms by which the variants that contribute to genetic risk for SCZ affect brain connectivity and development patterns. EEG coherence measures functional connectivity by the degree of synchrony in oscillatory activity between two brain regions, with increased coherence indicating functional integration between these brain regions and decreased coherence reflecting less correlated neural activity[9,10] Stated another way, EEG coherence reflects communication between distinct brain regions, which facilitate cognition and behavior[11,12,13,14].

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Results

Conclusion