Genome-wide interaction study with major depression identifies novel variants associated with cognitive function

被引：33

作者：

Thalamuthu, Anbupalam ^{[1
]}

Mills, Natalie T. ^{[2
]}

Berger, Klaus ^{[3
]}

Minnerup, Heike ^{[3
]}

Grotegerd, Dominik ^{[4
]}

Dannlowski, Udo ^{[4
]}

Meinert, Susanne ^{[4
,5
]}

Opel, Nils ^{[4
]}

Repple, Jonathan ^{[4
]}

Gruber, Marius ^{[4
]}

Stein, Frederike ^{[6
]}

Brosch, Katharina ^{[6
]}

Meller, Tina ^{[6
]}

Pfarr, Julia-Katharina ^{[6
]}

Forstner, Andreas J. ^{[7
,8
,9
,10
]}

Hoffmann, Per ^{[7
,8
]}

Nothen, Markus M. ^{[7
,8
]}

Witt, Stephanie ^{[11
]}

Rietschel, Marcella ^{[11
]}

Kircher, Tilo ^{[6
]}

Adams, Mark ^{[12
]}

McIntosh, Andrew M. ^{[12
]}

Porteous, David J. ^{[13
]}

Deary, Ian J. ^{[14
]}

Hayward, Caroline ^{[15
]}

Campbell, Archie ^{[13
]}

Grabe, Hans Joergen ^{[16
,17
]}

Teumer, Alexander ^{[18
]}

Homuth, Georg ^{[19
]}

Van der Auwera-Palitschka, Sandra ^{[16
,17
]}

Schubert, K. Oliver ^{[2
,20
]}

Baune, Bernhard T. ^{[2
,21
,22
,23
]}

机构：

[1] Univ New South Wales, Ctr Hlth Brain Ageing CHeBA, Sch Psychiat, Sydney, NSW, Australia

[2] Univ Adelaide, Adelaide Med Sch, Discipline Psychiat, Adelaide, SA, Australia

[3] Univ Munster, Inst Epidemiol & Social Med, Munster, Germany

[4] Univ Munster, Inst Translat Psychiat, Munster, Germany

[5] Univ Munster, Inst Translat Neurosci, Munster, Germany

[6] Philipps Univ Marburg UKGM Marburg, Dept Psychiat & Psychotherapy, Marburg, Germany

[7] Univ Bonn, Sch Med, Inst Human Genet, Bonn, Germany

[8] Univ Hosp Bonn, Bonn, Germany

[9] Res Ctr Julich, Inst Neurosci & Med INM 1, Julich, Germany

[10] Univ Marburg, Ctr Human Genet, Marburg, Germany

[11] Heidelberg Univ, Fac Med Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany

[12] Univ Edinburgh, Div Psychiat, Edinburgh, Midlothian, Scotland

[13] Univ Edinburgh, Western Gen Hosp, Ctr Genom & Expt Med, Inst Genet & Canc, Edinburgh EH4 2XU, Midlothian, Scotland

[14] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland

[15] Univ Edinburgh, Western Gen Hosp, Inst Genet & Canc, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland

[16] Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany

[17] German Ctr Neurodegenerat Dis DZNE, Site Rostock Greifswald, Greifswald, Germany

[18] Univ Med Greifswald, Inst Community Med, Greifswald, Germany

[19] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany

[20] Northern Adelaide Mental Hlth Serv, Salisbury, SA, Australia

[21] Univ Munster, Univ Hosp Munster, Dept Psychiat & Psychotherapy, Munster, Germany

[22] Univ Melbourne, Melbourne Med Sch, Dept Psychiat, Melbourne, Vic, Australia

[23] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic, Australia

来源：

MOLECULAR PSYCHIATRY | 2022年 / 27卷 / 02期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

EXECUTIVE FUNCTION; WORKING-MEMORY; METAANALYSIS; DYSFUNCTION; GWAS; DISORDERS; REGULATOR; TADALAFIL; RECOVERY; HEALTH;

D O I：

10.1038/s41380-021-01379-5

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Major Depressive Disorder (MDD) often is associated with significant cognitive dysfunction. We conducted a meta-analysis of genome-wide interaction of MDD and cognitive function using data from four large European cohorts in a total of 3510 MDD cases and 6057 controls. In addition, we conducted analyses using polygenic risk scores (PRS) based on data from the Psychiatric Genomics Consortium (PGC) on the traits of MDD, Bipolar disorder (BD), Schizophrenia (SCZ), and mood instability (MIN). Functional exploration contained gene expression analyses and Ingenuity Pathway Analysis (IPA(R)). We identified a set of significantly interacting single nucleotide polymorphisms (SNPs) between MDD and the genome-wide association study (GWAS) of cognitive domains of executive function, processing speed, and global cognition. Several of these SNPs are located in genes expressed in brain, with important roles such as neuronal development (REST), oligodendrocyte maturation (TNFRSF21), and myelination (ARFGEF1). IPA(R) identified a set of core genes from our dataset that mapped to a wide range of canonical pathways and biological functions (MPO, FOXO1, PDE3A, TSLP, NLRP9, ADAMTS5, ROBO1, REST). Furthermore, IPA(R) identified upstream regulator molecules and causal networks impacting on the expression of dataset genes, providing a genetic basis for further clinical exploration (vitamin D receptor, beta-estradiol, tadalafil). PRS of MIN and meta-PRS of MDD, MIN and SCZ were significantly associated with all cognitive domains. Our results suggest several genes involved in physiological processes for the development and maintenance of cognition in MDD, as well as potential novel therapeutic agents that could be explored in patients with MDD associated cognitive dysfunction.

引用

页码：1111 / 1119

页数：9

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