Transcriptome-based polygenic score links depression-related corticolimbic gene expression changes to sex-specific brain morphology and depression risk

Miles, Amy; Santos, Fernanda Caroline dos; Byrne, Enda M.; Rentería, Miguel E.; McIntosh, Andrew M.; Adams, Mark J.; Pistis, Giorgio; Castelao, Enrique; Preisig, Martin; Baune, Bernhard T.; Schubert, Klaus Oliver; Lewis, Cathryn M.; Jones, L. A.; Jones, Ian; Uher, Rudolf; Smoller, Jordan W; Perlis, Roy H.; Levinson, Douglas F.; Potash, James B.; Weissman, Myrna M.; Shi, Jianxin; Penninx, Brenda W. J. H.; Boomsma, Dorret I.; Hamilton, Steven P.; Sibille, Etienne; Hariri, Ahmad R.; Nikolova, Yuliya S.

doi:10.1038/s41386-021-01189-x

Cited by 7 publications

(5 citation statements)

References 44 publications

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“…In agreement with a previous study in depression [ 66 ], TRSs were uncorrelated with genome-wide PRS. This lack of correlation may highlight that TRSs based on observed gene expression data capture more information than cis-eQTL genetic risk variants, such as trans-eQTL, environment factors or epigenetics, as well as interaction effects between genes and environment, among others.…”

Section: Discussionsupporting

confidence: 93%

Transcriptomic risk scores for attention deficit/hyperactivity disorder

et al. 2023

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Attention deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder. We performed a transcriptome-wide association study (TWAS) using the latest genome-wide association study (GWAS) meta-analysis, in 38,691 individuals with ADHD and 186,843 controls, and 14 gene-expression reference panels across multiple brain tissues and whole blood. Based on TWAS results, we selected subsets of genes and constructed transcriptomic risk scores (TRSs) for the disorder in peripheral blood mononuclear cells of individuals with ADHD and controls. We found evidence of association between ADHD and TRSs constructed using expression profiles from multiple brain areas, with individuals with ADHD carrying a higher burden of TRSs than controls. TRSs were uncorrelated with the polygenic risk score (PRS) for ADHD and, in combination with PRS, improved significantly the proportion of variance explained over the PRS-only model. These results support the complementary predictive potential of genetic and transcriptomic profiles in blood and underscore the potential utility of gene expression for risk prediction and deeper insight in molecular mechanisms underlying ADHD.

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Section: Discussionsupporting

confidence: 93%

Transcriptomic risk scores for attention deficit/hyperactivity disorder

et al. 2023

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“…We did not observe sex differences in depression symptom severity, likely because the HCP data reflect a largely non-clinical sample (Miles et al, 2021). Nonetheless, we noted sex differences in sgACC connectivity markers both in association with polygenic risk and depression severity.…”

Section: Discussionmentioning

confidence: 77%

“…We did not observe sex differences in depression symptom severity, likely because the HCP data reflect a largely non-clinical sample (Miles et al, 2021).…”

Section: Sex Differences In Sgacc Rsfc Markers Of Depression Risk And...mentioning

confidence: 67%

Polygenic risk for depression and resting state functional connectivity of subgenual anterior cingulate cortex in young adults

Chen,

Li,

Luo

et al. 2024

Preprint

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Genetic variants may confer risks for depression by modulating brain structure and function. Prior evidence has underscored a key role of the subgenual anterior cingulate cortex (sgACC) in depression. Here, we built on the literature and examined how the resting state functional connectivity (rsFC) of the sgACC was associated with polygenic risks for depression. We followed published routines and computed seed-based whole-brain sgACC rsFC and polygenic risk scores (PRS) of 717 young adults curated from the Human Connectome Project. We performed whole-brain regression against PRS and severity of depression symptoms in a single model for all subjects and for men and women alone, controlling for age, sex (for all), race, severity of alcohol use, and household income, and evaluated the results at a corrected threshold. We found lower sgACC rsFC with the default mode network and frontal regions in association with PRS and lower sgACC-cerebellar rsFC in association with depression severity. We also noted sex differences in the connectivity correlates of PRS and depression severity. In an additional set of analyses, we observed a significant correlation between PRS and somatic complaints score and altered sgACC-somatosensory cortical connectivity in link with the severity of somatic complaints. Our findings collectively highlighted the pivotal role of distinct sgACC-based networks in the genetic predisposition to depression and the clinical manifestation of depression. Distinguishing the risk from severity markers of depression may have implications in developing early and effective treatments for individuals at risk for depression.

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“…The duration of depression is related to the degree of cognitive impairment (Pabel et al ., 2018 ). MDD has been associated with cortical transcriptomic changes and there are sex differences in the effects of cortical gene expression on brain morphology (Miles et al ., 2021 ). This study suggests that transcriptome-based polygenic score was associated with smaller amygdala volume and lower prefrontal gyrification across sexes in female patients, and related to hypergyrification in temporal and occipital areas in male patients.…”

Section: Discussionmentioning

confidence: 99%

Sex differences of brain cortical structure in major depressive disorder

Mou,

Zheng,

Long

et al. 2023

Psychoradiology

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Background Major depressive disorder (MDD) has different clinical presentations in males and females. However, the neuroanatomical mechanisms underlying these sex differences are not fully understood. Methods High-resolution T1-weighted images were acquired from 61 patients with MDD and 61 healthy controls (36 females and 25 males, both). The sex differences in cortical thickness (CT) and surface area (SA) were obtained using the FreeSurfer software and compared between every two groups by post-hoc test. Spearman correlation analysis was also performed to explore the relationships between these regions and clinical characteristics. Results In male patients with MDD, the CT of the right precentral was thinner compared to female patients, although not survive Bonferroni correction. The SA of several regions, including right superior frontal, medial orbitofrontal gyrus, inferior frontal gyrus triangle, superior temporal, middle temporal, lateral occipital gyrus, and inferior parietal lobule in female patients with MDD was smaller than that in male patients (p < 0.01 after Bonferroni correction). In female patients, the SA of the right superior temporal (r = 0.438, p = 0.008), middle temporal (r = 0.340, p = 0.043), and lateral occipital gyrus (r = 0.372, p = 0.025) were positively correlated with illness duration. Conclusion The current study provides evidence of sex differences in CT and SA in patients with MDD, which may improve our understanding of the sex-specific neuroanatomical changes in the development of MDD.

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Transcriptome-based polygenic score links depression-related corticolimbic gene expression changes to sex-specific brain morphology and depression risk

Abstract: Transcriptome-based polygenic score links depression-related corticolimbic gene expression changes to sex-specific brain morphology and depression risk', Neuropsychopharmacology.

Cited by 7 publications

References 44 publications

Transcriptomic risk scores for attention deficit/hyperactivity disorder

Transcriptomic risk scores for attention deficit/hyperactivity disorder

Polygenic risk for depression and resting state functional connectivity of subgenual anterior cingulate cortex in young adults

Sex differences of brain cortical structure in major depressive disorder

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