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000284046 041__ $$aEnglish
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000284046 1001_ $$00000-0002-0538-4774$$aShen, Xueyi$$b0
000284046 245__ $$aAssociation between polygenic risk for Major Depression and brain structure in a mega-analysis of 50,975 participants across 11 studies.
000284046 260__ $$a[London]$$bSpringer Nature$$c2026
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000284046 520__ $$aMajor Depression (MD) is a prevalent, disabling and life-limiting condition. The neurobiological associations of genetic risk for MD remain under-explored in large samples, with no comprehensive mega-analysis conducted to date. Our study analysed data from 11 separate studies, encompassing 50,975 participants from the ENIGMA Major Depressive Disorder Working Group. We developed highly consistent genetic and neuroimaging protocols and applied these throughout all participating studies, together with rigorous genetic methods to remove overlap between the polygenic risk scores (PRS) training and testing samples. Elevated PRS for MD correlated with lower intracranial volume and lower global measure of cortical surface area (βICV = -0.017, pICV = 1.97 × 10-6; βSurf = -0.013, pSurf = 4.5 × 10-4; pFDR < 3.62 × 10-4). The most significant cortical association was observed in the surface area of the frontal lobe (β = -0.011, p = 2.85 × 10-6, pFDR = 1.42 × 10-5), particularly in the left medial orbito-frontal gyrus (β = -0.021, p = 9.48 × 10-8, pFDR = 1.25 × 10-5). In subcortical regions, lower volumes of the thalamus, hippocampus, and pallidum correlated with higher PRS of MD (β ranged from -0.011 to -0.015, p ranged from 0.002-1.73 × 10-5, pFDR < 0.006). In a subsample of young individuals only (<25 years old, N = 5570), although there were no FDR-significant findings, directions of effects were highly consistent between the analyses of cortical surface areas in youth and the full sample (71.2% in the same direction, exact binomial test p-value = 7.56 × 10-4). Subsequent Mendelian randomisation analysis revealed potentially causal effects of smaller left hippocampal volume on higher liability for MD (Inverse variance weighted analysis β = -0.064, p = 8.04 × 10-3, pFDR = 0.04). Our findings represent an example of how extensive international collaborations can significantly advance our neurogenetic understanding of MD and give insights to avenues for early interventions in those at high risk for developing MD.
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000284046 650_2 $$2MeSH$$aHumans
000284046 650_2 $$2MeSH$$aMajor Depressive Disorder: genetics
000284046 650_2 $$2MeSH$$aMajor Depressive Disorder: pathology
000284046 650_2 $$2MeSH$$aMultifactorial Inheritance: genetics
000284046 650_2 $$2MeSH$$aMale
000284046 650_2 $$2MeSH$$aFemale
000284046 650_2 $$2MeSH$$aGenetic Predisposition to Disease: genetics
000284046 650_2 $$2MeSH$$aBrain: pathology
000284046 650_2 $$2MeSH$$aAdult
000284046 650_2 $$2MeSH$$aMagnetic Resonance Imaging: methods
000284046 650_2 $$2MeSH$$aGenome-Wide Association Study: methods
000284046 650_2 $$2MeSH$$aMiddle Aged
000284046 650_2 $$2MeSH$$aNeuroimaging: methods
000284046 650_2 $$2MeSH$$aRisk Factors
000284046 650_2 $$2MeSH$$aPolymorphism, Single Nucleotide: genetics
000284046 7001_ $$00000-0002-4117-1143$$aToenders, Yara J$$b1
000284046 7001_ $$00000-0001-9647-3723$$aHan, Laura K M$$b2
000284046 7001_ $$0P:(DE-2719)9002604$$aWeihs, Antoine$$b3
000284046 7001_ $$aAlexander, Nina$$b4
000284046 7001_ $$00000-0002-2917-5889$$aAndlauer, Till F M$$b5
000284046 7001_ $$00000-0002-0526-8095$$aBrosch, Katharina$$b6
000284046 7001_ $$00000-0002-1876-6368$$aForstner, Andreas J$$b7
000284046 7001_ $$aGrotegerd, Dominik$$b8
000284046 7001_ $$00000-0001-6541-3795$$aHahn, Tim$$b9
000284046 7001_ $$aHermesdorf, Marco$$b10
000284046 7001_ $$aHosten, Norbert$$b11
000284046 7001_ $$00000-0003-2485-2374$$aJamalabadi, Hamidreza$$b12
000284046 7001_ $$00000-0003-2177-7161$$aMeinert, Susanne$$b13
000284046 7001_ $$00000-0002-3697-6617$$aMilaneschi, Yuri$$b14
000284046 7001_ $$00000-0001-8523-3628$$aSämann, Philipp G$$b15
000284046 7001_ $$aStein, Frederike$$b16
000284046 7001_ $$00000-0002-1147-7539$$aStolicyn, Aleks$$b17
000284046 7001_ $$aTeutenberg, Lea$$b18
000284046 7001_ $$aThng, Gladi$$b19
000284046 7001_ $$00000-0002-3599-6018$$aAdams, Mark J$$b20
000284046 7001_ $$00000-0003-4912-8307$$aThomas-Odenthal, Florian$$b21
000284046 7001_ $$aUsemann, Paula$$b22
000284046 7001_ $$aVölker, Uwe$$b23
000284046 7001_ $$0P:(DE-2719)2810491$$aWittfeld, Katharina$$b24$$udzne
000284046 7001_ $$00000-0001-7064-9487$$aHerrera-Rivero, Marisol$$b25
000284046 7001_ $$aJiang, Yunxuan$$b26
000284046 7001_ $$aTian, Chao$$b27
000284046 7001_ $$aTeam, 23andMe Research$$b28$$eCollaboration Author
000284046 7001_ $$00000-0002-0865-8427$$aGroenewold, Nynke A$$b29
000284046 7001_ $$aKoopowitz, Sheri-Michelle$$b30
000284046 7001_ $$aStrike, Lachlan T$$b31
000284046 7001_ $$00000-0002-0623-3759$$aDannlowski, Udo$$b32
000284046 7001_ $$aJansen, Andreas$$b33
000284046 7001_ $$00000-0002-2514-2625$$aKircher, Tilo$$b34
000284046 7001_ $$00000-0002-0749-7473$$aNenadić, Igor$$b35
000284046 7001_ $$aSim, Kang$$b36
000284046 7001_ $$00000-0002-9837-0944$$aStraube, Benjamin$$b37
000284046 7001_ $$aVölzke, Henry$$b38
000284046 7001_ $$00000-0001-7218-7810$$aStein, Dan J$$b39
000284046 7001_ $$00000-0003-1382-380X$$aMedland, Sarah E$$b40
000284046 7001_ $$aBerger, Klaus$$b41
000284046 7001_ $$0P:(DE-2719)2811781$$aGrabe, Hans$$b42$$udzne
000284046 7001_ $$00000-0002-0564-2497$$aKrug, Axel$$b43
000284046 7001_ $$00000-0002-6357-615X$$aMcMahon, Katie L$$b44
000284046 7001_ $$00000-0003-4506-0579$$ade Zubicaray, Greig$$b45
000284046 7001_ $$aPozzi, Elena$$b46
000284046 7001_ $$aVeltman, Dick J$$b47
000284046 7001_ $$aThomopoulos, Sophia I$$b48
000284046 7001_ $$aJahanshad, Neda$$b49
000284046 7001_ $$aThompson, Paul M$$b50
000284046 7001_ $$00000-0001-9822-048X$$aSchmaal, Lianne$$b51
000284046 7001_ $$00000-0002-0198-4588$$aMcIntosh, Andrew M$$b52
000284046 7001_ $$00000-0002-4505-8869$$aWhalley, Heather C$$b53
000284046 7001_ $$agroup, ENIGMA MDD working$$b54$$eCollaboration Author
000284046 7001_ $$ade Zubicaray, Greig$$b55$$eContributor
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