Department of Biomedicine

TY - JOUR

T1 - Transcriptome-based polygenic score links depression-related corticolimbic gene expression changes to sex-specific brain morphology and depression risk

AU - Miles, Amy E

AU - Dos Santos, Fernanda C

AU - Byrne, Enda M

AU - Renteria, Miguel E

AU - McIntosh, Andrew M

AU - Adams, Mark J

AU - Pistis, Giorgio

AU - Castelao, Enrique

AU - Preisig, Martin

AU - Baune, Bernhard T

AU - Schubert, K Oliver

AU - Lewis, Cathryn M

AU - Jones, Lisa A

AU - Jones, Ian

AU - Uher, Rudolf

AU - Smoller, Jordan W

AU - Perlis, Roy H

AU - Levinson, Douglas F

AU - Potash, James B

AU - Weissman, Myrna M

AU - Shi, Jianxin

AU - Lewis, Glyn

AU - Penninx, Brenda W J H

AU - Boomsma, Dorret I

AU - Hamilton, Steven P

AU - Sibille, Etienne

AU - Hariri, Ahmad R

AU - Nikolova, Yuliya S

AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

AU - Mattheisen, Manuel

AU - Agerbo, Esben

AU - Buttenschøn, Henriette Nørmølle

AU - Christensen, Jane Hvarregaard

AU - Grove, Jakob

AU - Pedersen, Carsten Bøcker

AU - Pedersen, Marianne Giørtz

AU - Qvist, Per

AU - Mortensen, Preben Bo

AU - Børglum, Anders

N1 - © 2021. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.

PY - 2021/12

Y1 - 2021/12

N2 - Studies in post-mortem human brain tissue have associated major depressive disorder (MDD) with cortical transcriptomic changes, whose potential in vivo impact remains unexplored. To address this translational gap, we recently developed a transcriptome-based polygenic risk score (T-PRS) based on common functional variants capturing 'depression-like' shifts in cortical gene expression. Here, we used a non-clinical sample of young adults (n = 482, Duke Neurogenetics Study: 53% women; aged 19.8 ± 1.2 years) to map T-PRS onto brain morphology measures, including Freesurfer-derived subcortical volume, cortical thickness, surface area, and local gyrification index, as well as broad MDD risk, indexed by self-reported family history of depression. We conducted side-by-side comparisons with a PRS independently derived from a Psychiatric Genomics Consortium (PGC) MDD GWAS (PGC-PRS), and sought to link T-PRS with diagnosis and symptom severity directly in PGC-MDD participants (n = 29,340, 59% women; 12,923 MDD cases, 16,417 controls). T-PRS was associated with smaller amygdala volume in women (t = -3.478, p = 0.001) and lower prefrontal gyrification across sexes. In men, T-PRS was associated with hypergyrification in temporal and occipital regions. Prefrontal hypogyrification mediated a male-specific indirect link between T-PRS and familial depression (b = 0.005, p = 0.029). PGC-PRS was similarly associated with lower amygdala volume and cortical gyrification; however, both effects were male-specific and hypogyrification emerged in distinct parietal and temporo-occipital regions, unassociated with familial depression. In PGC-MDD, T-PRS did not predict diagnosis (OR = 1.007, 95% CI = [0.997-1.018]) but correlated with symptom severity in men (rho = 0.175, p = 7.957 × 10-4) in one cohort (N = 762, 48% men). Depression-like shifts in cortical gene expression have sex-specific effects on brain morphology and may contribute to broad depression vulnerability in men.

AB - Studies in post-mortem human brain tissue have associated major depressive disorder (MDD) with cortical transcriptomic changes, whose potential in vivo impact remains unexplored. To address this translational gap, we recently developed a transcriptome-based polygenic risk score (T-PRS) based on common functional variants capturing 'depression-like' shifts in cortical gene expression. Here, we used a non-clinical sample of young adults (n = 482, Duke Neurogenetics Study: 53% women; aged 19.8 ± 1.2 years) to map T-PRS onto brain morphology measures, including Freesurfer-derived subcortical volume, cortical thickness, surface area, and local gyrification index, as well as broad MDD risk, indexed by self-reported family history of depression. We conducted side-by-side comparisons with a PRS independently derived from a Psychiatric Genomics Consortium (PGC) MDD GWAS (PGC-PRS), and sought to link T-PRS with diagnosis and symptom severity directly in PGC-MDD participants (n = 29,340, 59% women; 12,923 MDD cases, 16,417 controls). T-PRS was associated with smaller amygdala volume in women (t = -3.478, p = 0.001) and lower prefrontal gyrification across sexes. In men, T-PRS was associated with hypergyrification in temporal and occipital regions. Prefrontal hypogyrification mediated a male-specific indirect link between T-PRS and familial depression (b = 0.005, p = 0.029). PGC-PRS was similarly associated with lower amygdala volume and cortical gyrification; however, both effects were male-specific and hypogyrification emerged in distinct parietal and temporo-occipital regions, unassociated with familial depression. In PGC-MDD, T-PRS did not predict diagnosis (OR = 1.007, 95% CI = [0.997-1.018]) but correlated with symptom severity in men (rho = 0.175, p = 7.957 × 10-4) in one cohort (N = 762, 48% men). Depression-like shifts in cortical gene expression have sex-specific effects on brain morphology and may contribute to broad depression vulnerability in men.

KW - AMYGDALA

KW - ASSOCIATION

KW - DISORDERS

KW - DSM-IV

KW - ONSET

KW - Genetic Predisposition to Disease

KW - Humans

KW - Transcriptome

KW - Male

KW - Multifactorial Inheritance

KW - Depressive Disorder, Major/genetics

KW - Young Adult

KW - Brain/diagnostic imaging

KW - Depression/genetics

KW - Female

U2 - 10.1038/s41386-021-01189-x

DO - 10.1038/s41386-021-01189-x

M3 - Journal article

C2 - 34588609

VL - 46

SP - 2304

EP - 2311

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

SN - 0893-133X

IS - 13

ER -