Sex Differences in the Brain Transcriptome Related to Alcohol Effects and Alcohol Use Disorder

Hitzemann, Robert; Bergeson, Susan E.; Berman, Ari; Bubier, Jason A.; Chesler, Elissa J.; Finn, Deborah A.; Hein, Matthew; Hoffman, Paula L.; Holmes, Andrew; Kisby, Brent R.; Lockwood, Denesa R.; Lodowski, Kerrie H.; McManus, Michelle; Owen, Julie A.; Ozburn, Angela R.; Panthagani, Praneetha; Ponomarev, Igor; Saba, Laura; Tabakoff, Boris; Walchale, Aashlesha; Williams, Robert W.; Phillips, Tamara J.

doi:10.1016/j.biopsych.2021.04.016

Cited by 35 publications

(26 citation statements)

References 94 publications

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“…These data are consistent with the neuroimmune hypothesis of alcohol use disorder (AUD) (65). Sex differences in the alcohol-induced neuroimmune signaling are discussed elsewhere (64). The second point of emphasis are the data pointing to the involvement of the ECM.…”

Section: Hdid Selected Lines and Gene Expressionsupporting

confidence: 77%

“…For male genes with decreased variance (N = 103), there were significant enrichments in GO categories associated with biological adhesion and extracellular part. From the perspective of the DV metric, which is closely aligned with network connectivity, the female and male data were largely mirror images" (64).…”

Section: Hdid Selected Lines and Gene Expressionmentioning

confidence: 97%

“…Beginning with Colville et al (61) (see below), we introduced the differential variability (DV) metric into our analysis strategy [see (62)(63)(64)]. This computationally simple procedure identifies those genes that are likely to show a change in network connectivity.…”

Section: Hdid Selected Lines and Gene Expressionmentioning

confidence: 99%

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On the Use of Heterogeneous Stock Mice to Map Transcriptomes Associated With Excessive Ethanol Consumption

et al. 2021

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We and many others have noted the advantages of using heterogeneous (HS) animals to map genes and gene networks associated with both behavioral and non-behavioral phenotypes. Importantly, genetically complex Mus musculus crosses provide substantially increased resolution to examine old and new relationships between gene expression and behavior. Here we report on data obtained from two HS populations: the HS/NPT derived from eight inbred laboratory mouse strains and the HS-CC derived from the eight collaborative cross inbred mouse strains that includes three wild-derived strains. Our work has focused on the genes and gene networks associated with risk for excessive ethanol consumption, individual variation in ethanol consumption and the consequences, including escalation, of long-term ethanol consumption. Background data on the development of HS mice is provided, including advantages for the detection of expression quantitative trait loci. Examples are also provided of using HS animals to probe the genes associated with ethanol preference and binge ethanol consumption.

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Section: Hdid Selected Lines and Gene Expressionsupporting

confidence: 77%

Section: Hdid Selected Lines and Gene Expressionmentioning

confidence: 97%

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On the Use of Heterogeneous Stock Mice to Map Transcriptomes Associated With Excessive Ethanol Consumption

et al. 2021

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“…Instead, we speculate that the expression patterns of autosomal variants different across the sexes [35][36][37] may account for the modulatory effects of sex. Also, in line with this speculation, recent literature highlights sex differences in brain transcriptomes related to schizophrenia and alcohol effects 38,39 . It remains to be tested whether the modulatory effects last in the later development.…”

Section: Discussionsupporting

confidence: 52%

Gene, the Sexual Brain, and Cognition: Machine-Predicted Brain Sex Score Explains Individual Differences in Cognitive Development and Genetic Influence.

Kim¹,

Joo²,

Ahn³

et al. 2021

Preprint

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Sex impacts the development of the brain and cognition differently across individuals. We investigated the biological underpinnings of the individual variability of sexual dimorphism in the brain and its impact on cognitive development. In prepubertal children (N=9,658, ages 9~10 years old; the Adolescent Brain Cognitive Development study), we tested whether the individual difference in brain sex development was related to that in cognitive development, known to be influenced by genetic factors. We estimated an individual’s brain sex score from machine learning models trained on brain morphometry and diffusion white matter connectomes that accurately classified the biological sex with a test ROC-AUC of 93.32%. A greater brain sex score correlated significantly with greater intelligence (Pfdr<0.001, ηp2=0.034~0.050; adjusted for covariates) and higher cognitive genome-wide polygenic scores (GPSs) (Pfdr<0.001, ηp2<0.005). Structural equation models revealed that the GPS-intelligence association was modulated by the brain sex score, such that a brain with a higher maleness score (or a lower femaleness score) mediated a positive GPS effect on intelligence (indirect effects=0.006~0.009; P=0.002~0.022; sex-stratified analysis). The novel gene-brain-cognition relationship reported in this study presents a biological pathway to the individual and sex differences in the brain and cognitive development in preadolescence.

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“…Alternatively, we speculate that the different expression patterns of autosomal variants across sex (Boraska et al, 2012;Wijchers & Festenstein, 2011;Zuo et al, 2015) may account for the modulatory effects of sex. Indeed, in line with this speculation, recent literature highlights sex differences in brain transcriptomes related to schizophrenia and alcohol effects (Hitzemann et al, 2021;Hoffman et al, 2022). Future research may test the association between sex differences in genetic expression in the brain and neurocognitive development.…”

Section: Discussionmentioning

confidence: 73%

The sexual brain, genes, and cognition: A machine‐predicted brain sex score explains individual differences in cognitive intelligence and genetic influence in young children

Kim

Joo

Ahn

et al. 2022

Human Brain Mapping

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Sex impacts the development of the brain and cognition differently across individuals. However, the literature on brain sex dimorphism in humans is mixed. We aim to investigate the biological underpinnings of the individual variability of sexual dimorphism in the brain and its impact on cognitive performance. To this end, we tested whether the individual difference in brain sex would be linked to that in cognitive performance that is influenced by genetic factors in prepubertal children (N = 9,658, ages 9-10 years old; the Adolescent Brain Cognitive Development study). To capture the interindividual variability of the brain, we estimated the probability of being male or female based on the brain morphometry and connectivity features using machine learning (herein called a brain sex score). The models accurately classified the biological sex with a test ROC-AUC of 93.32%. As a result, a greater brain sex score correlated significantly with greater intelligence (p fdr < .001, η 2 p = .011-.034; adjusted for covariates) and higher cognitive genome-wide polygenic scores (GPSs) (p fdr < .001, η 2 p < .005). Structural equation models revealed that the GPS-intelligence association was significantly modulated by the brain sex score, such that a brain with a higher maleness score (or a lower femaleness score) mediated a positive GPS effect on intelligence (indirect effects = .006-.009; p = .002-.022; sex-stratified analysis). The finding of the sex modulatory effect on the gene-brain-cognition relationship presents a likely biological pathway to the individual and sex differences in the brain and cognitive performance in preadolescence.

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Sex Differences in the Brain Transcriptome Related to Alcohol Effects and Alcohol Use Disorder

Cited by 35 publications

References 94 publications

On the Use of Heterogeneous Stock Mice to Map Transcriptomes Associated With Excessive Ethanol Consumption

On the Use of Heterogeneous Stock Mice to Map Transcriptomes Associated With Excessive Ethanol Consumption

Gene, the Sexual Brain, and Cognition: Machine-Predicted Brain Sex Score Explains Individual Differences in Cognitive Development and Genetic Influence.

The sexual brain, genes, and cognition: A machine‐predicted brain sex score explains individual differences in cognitive intelligence and genetic influence in young children

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