Association of Whole-Genome and NETRIN1 Signaling Pathway–Derived Polygenic Risk Scores for Major Depressive Disorder and White Matter Microstructure in the UK Biobank

Barbu, Miruna C.; Zeng, Yanni; Shen, Xueyi; Cox, Simon R.; Gibson, Jude; Johnstone, Mandy; Haley, Chris; Lawrie, Stephen M.; Whalley, Heather; Wray, Naomi R.; Ripke, Stephan; Mattheisen, Manuel; Trzaskowski, Maciej; Byrne, Enda M.; Abdellaoui, Abdel; Adams, Mark; Agerbo, Esben; Air, Tracy; Andlauer, Till F. M.; Bacanu, Silviu‐Alin; Bækvad‐Hansen, Marie; Beekman, Aartjan T.F.; Bigdeli, Tim B.; Binder, Elisabeth B.; Blackwood, Douglas; Bryois, Julien; Buttenschøn, Henriette Nørmølle; Bybjerg‐Grauholm, Jonas; Cai, Na; Castelao, Enrique; Christensen, Jane Hvarregaard; Clarke, Toni‐Kim; Coleman, Jonathan; Colodro‐Conde, Lucía; Couvy‐Duchesne, Baptiste; Craddock, Nick; Crawford, Gregory E.; Davies, Gail; Deary, Ian J.; Degenhardt, Franziska; Derks, Eske M.; Direk, Neşe; Dolan, Conor V.; Dunn, Erin C.; Eley, Thalia C.; Escott‐Price, Valentina; Kiadeh, Farnush Farhadi Hassan; Finucane, Hilary; Forstner, Andreas J.; Frank, Josef; Gaspar, Héléna A.; Gill, Michael; Goes, Fernando S.; Gordon, Scott D.; Grove, Jakob; Hall, Lynsey S.; Hansen, Christine Søholm; Hansen, Thomas; Herms, Stefan; Hickie, Ian B.; Hoffmann, Per; Homuth, Georg; Horn, Carsten; Hottenga, Jouke‐Jan; Hougaard, David M.; Ising, Marcus; Jansen, Rick; Jorgenson, Eric; Knowles, James A.; Kohane, Isaac S.; Kraft, Julia; Kretzschmar, Warren W.; Krogh, Jesper; Kutalik, Zoltán; Li, Yihan; Lind, Penelope A.; MacIntyre, Donald J.; MacKinnon, Dean F.; Maier, Robert; Maier, Wolfgang; Marchini, Jonathan; Mbarek, Hamdi; McGrath, Patrick J.; McGuffin, Peter; Medland, Sarah E.; Mehta, Divya; Middeldorp, Christel M.; Mihailov, Evelin; Milaneschi, Yuri; Milani, Lili; Mondimore, Francis M.; Montgomery, Grant W.; Mostafavi, Sara; Mullins, Niamh; Nauck, Matthias; Ng, Bernard; Nivard, Michel G.; Nyholt, Dale R.; O’Reilly, Paul; Óskarsson, Högni; Owen, Michael John; Painter, Jodie N.; Pedersen, Carsten Bøcker; Pedersen, Marianne Giørtz; Peterson, Roseann E.; Pettersson, Erik; Peyrot, Wouter J.; Pistis, Giorgio; Posthuma, Daniëlle; Quiróz, Jorge A.; Qvist, Per; Rice, John P.; Riley, Brien P.; Rivera, Margarita; Mirza, Saira Saeed; Schoevers, Robert; Schulte, Eva C.; Shen, Lei; Shi, Jianxin; Shyn, Stanley I.; Sigurðsson, Engilbert; Sinnamon, Grant; Smit, Johannes H.; Smith, Daniel J.; Stefánsson, Hreinn; Steinberg, Stacy; Streit, Fabian; Strohmaier, Jana; Tansey, Katherine E.; Teismann, Henning; Teumer, Alexander; Thompson, Wesley; Thomson, Pippa A.; Thorgeirsson, Thorgeir E.; Traylor, Matthew; Treutlein, Jens; Trubetskoy, Vassily; Uitterlinden, André G.; Umbricht, Daniel; Auwera, Sandra Van der; Hemert, Albert M. van; Viktorin, Alexander; Visscher, Peter M.; Wang, Yunpeng; Webb, Bradley T.; Weinsheimer, Shantel; Wellmann, Jürgen; Willemsen, Gonneke; Witt, Stephanie H.; Wu, Yang; Xi, Hualin Simon; Yang, Jian; Zhang, Futao; Arolt, Volker; Baune, Bernhard T.; Berger, Klaus; Boomsma, Dorret I.; Cichon, Sven; Dannlowski, Udo; Geus, E.J.C. de; DePaulo, J. Raymond; Domenici, Enrico; Domschke, Katharina; Esko, Tõnu; Grabe, Hans J.; Hamilton, Steven P.; Hayward, Caroline; Heath, Andrew C.; Kendler, Kenneth S.; Kloiber, Stefan; Lewis, Glyn; Li, Qingqin; Lucae, Susanne; Madden, Pamela A. F.; Magnusson, Patrik K. E.; Martin, Nicholas G.; McIntosh, Andrew M.; Metspalu, Andres; Mors, Ole; Mortensen, Preben Bo; Müller‐Myhsok, Bertram; Nordentoft, Merete; Nöthen, Markus M.; O’Donovan, Michael; Paciga, Sara A.; Pedersen, Nancy L.; Penninx, Brenda W. J. H.; Perlis, Roy H.; Porteous, David J.; Potash, James B.; Preisig, Martin; Rietschel, Marcella; Schaefer, Catherine; Schulze, Thomas G.; Smoller, Jordan W.; Stefánsson, Kāri; Tiemeier, Henning; Uher, Rudolf; Völzke, Henry; Weissman, Myrna M.; Werge, Thomas; Lewis, Cathryn M.; Levinson, Douglas F.; Breen, Gerome; Børglum, Anders; Sullivan, Patrick F.; Agee, Michelle; Alipanahi, Babak; Auton, Adam; Bell, Robert K.; Bryc, Katarzyna; Elson, Sarah L.; Fontanillas, Pierre; Furlotte, Nicholas A.; Hinds, David A.; Huber, Karen E.; Kleinman, Aaron; Litterman, Nadia K.; McCreight, Jennifer C.; McIntyre, Matthew H.; Mountain, Joanna L.; Noblin, Elizabeth S.; Northover, Carrie A. M.; Pitts, Steven J.; Sathirapongsasuti, J. Fah; Sazonova, Olga V.; Shelton, Janie F.; Shringarpure, Suyash; Tian, Chao; Tung, Joyce Y.; Vacic, Vladimir; Wilson, Catherine H.

doi:10.1016/j.bpsc.2018.07.006

Cited by 14 publications

(18 citation statements)

References 40 publications

(56 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results could therefore explain why thalamic radiations are one of the most replicated findings in either lifetime or cross-sectional case-control studies of MDD 16, 40, 41. First, lower microstructural integrity of the thalamic radiation may be particularly susceptible to the influence by early life factors 42, 43 and, second, they may relate to genetic predisposition to depression (17). Although the observational data in the current study did not allow for causal inferences, in future studies thalamic radiations may be a strong candidate as a causal biomarker for illness.…”

Section: Discussionsupporting

confidence: 52%

“…The mean age of participants was 63.06 years (SD = 7.44), and 47.14% were men. We then conducted further data quality control of the remaining participants by removing outliers 16, 17. Finally, the imaging data were merged with other relevant behavioral variables (Supplemental Figure S1).…”

Section: Methodsmentioning

confidence: 99%

“…In the current study, we first investigated the associations between these measures of depressive symptoms and white matter microstructure because of the growing evidence of an association between mood disorders and reductions of white matter microstructure in the limbic system, especially in the thalamic radiations 16, 17. These networks contain important tracts involved in emotional processing (18) and regulation (19).…”

mentioning

confidence: 99%

See 2 more Smart Citations

White Matter Microstructure and Its Relation to Longitudinal Measures of Depressive Symptoms in Mid- and Late Life

Shen

Adams

Ritakari

et al. 2019

Biological Psychiatry

Self Cite

View full text Add to dashboard Cite

BackgroundStudies of white matter microstructure in depression typically show alterations in individuals with depression, but they are frequently limited by small sample sizes and the absence of longitudinal measures of depressive symptoms. Depressive symptoms are dynamic, however, and understanding the neurobiology of different trajectories could have important clinical implications.MethodsWe examined associations between current and longitudinal measures of depressive symptoms and white matter microstructure (fractional anisotropy and mean diffusivity [MD]) in the UK Biobank Imaging Study. Depressive symptoms were assessed on two to four occasions over 5.9 to 10.7 years (n = 18,959 individuals on at least two occasions, n = 4444 on four occasions), from which we derived four measures of depressive symptomatology: cross-sectional measure at the time of scan and three longitudinal measures, namely trajectory and mean and intrasubject variance over time.ResultsDecreased white matter microstructure in the anterior thalamic radiation demonstrated significant associations across all four measures of depressive symptoms (MD: βs = .020–.029, pcorr < .030). The greatest effect sizes were seen between white matter microstructure and longitudinal progression (MD: βs = .030–.040, pcorr < .049). Cross-sectional symptom severity was particularly associated with decreased white matter integrity in association fibers and thalamic radiations (MD: βs = .015–.039, pcorr < .041). Greater mean and within-subject variance were mainly associated with decreased white matter microstructure within projection fibers (MD: βs = .019–.029, pcorr < .044).ConclusionsThese findings indicate shared and differential neurobiological associations with severity, course, and intrasubject variability of depressive symptoms. This enriches our understanding of the neurobiology underlying dynamic features of the disorder.

show abstract

Section: Discussionsupporting

confidence: 52%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

White Matter Microstructure and Its Relation to Longitudinal Measures of Depressive Symptoms in Mid- and Late Life

Shen

Adams

Ritakari

et al. 2019

Biological Psychiatry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recently, a UK Biobank study (n =~6400) found that the SNPs in the Netrin-1 signaling pathway conferring risk for major depression are associated with altered white matter microstructure in thalamic radiations, namely lower fractional anisotropy and higher mean diffusivity [72].…”

Section: Depressionmentioning

confidence: 99%

The Netrin-1/DCC guidance system: dopamine pathway maturation and psychiatric disorders emerging in adolescence

2019

View full text Add to dashboard Cite

Axon guidance molecules direct growing axons toward their targets, assembling the intricate wiring of the nervous system. One of these molecules, Netrin-1, and its receptor, DCC (deleted in colorectal cancer), has profound effects, in laboratory animals, on the adolescent expansion of mesocorticolimbic pathways, particularly dopamine. Now, a rapidly growing literature suggests that (1) these same alterations could occur in humans, and (2) genetic variants in Netrin-1 and DCC are associated with depression, schizophrenia, and substance use. Together, these findings provide compelling evidence that Netrin-1 and DCC influence mesocorticolimbic-related psychopathological states that emerge during adolescence.

show abstract

“…For the brain imaging sample, a quality check performed by UK Biobank ensured that no abnormal scans were included in subsequent analyses 23 . We additionally excluded individuals whose global measures for FA and MD lay more than three standard deviations from the sample mean 19,24 http://biobank.ctsu.ox.ac.uk/crystal/field. cgi?id=22001) were genotyped using the UK BiLEVE array (N = 49,949; http://biobank.ctsu.ox.ac.uk/crystal/refer.cgi?…”

Section: Study Populationmentioning

confidence: 99%

Expression quantitative trait loci-derived scores and white matter microstructure in UK Biobank: a novel approach to integrating genetics and neuroimaging

et al. 2020

Self Cite

View full text Add to dashboard Cite

Expression quantitative trait loci (eQTL) are genetic variants associated with gene expression. Using genome-wide genotype data, it is now possible to impute gene expression using eQTL mapping efforts. This approach can be used to analyse previously unexplored relationships between gene expression and heritable in vivo measures of human brain structural connectivity. Using large-scale eQTL mapping studies, we computed 6457 gene expression scores (eQTL scores) using genome-wide genotype data in UK Biobank, where each score represents a genetic proxy measure of gene expression. These scores were then tested for associations with two diffusion tensor imaging measures, fractional anisotropy (N FA = 14,518) and mean diffusivity (N MD = 14,485), representing white matter structural integrity. We found FDR-corrected significant associations between 8 eQTL scores and structural connectivity phenotypes, including global and regional measures (β absolute FA = 0.0339-0.0453; MD = 0.0308-0.0381) and individual tracts (β absolute FA = 0.0320-0.0561; MD = 0.0295-0.0480). The loci within these eQTL scores have been reported to regulate expression of genes involved in various brain-related processes and disorders, such as neurite outgrowth and Parkinson's disease (DCAKD, SLC35A4, SEC14L4, SRA1, NMT1, CPNE1, PLEKHM1, UBE3C). Our findings indicate that eQTL scores are associated with measures of in vivo brain connectivity and provide novel information not previously found by conventional genome-wide association studies. Although the role of expression of these genes regarding white matter microstructural integrity is not yet clear, these results suggest it may be possible, in future, to map potential trait-and disease-associated eQTL to in vivo brain connectivity and better understand the mechanisms of psychiatric disorders and brain traits, and their associated imaging findings.

show abstract

Association of Whole-Genome and NETRIN1 Signaling Pathway–Derived Polygenic Risk Scores for Major Depressive Disorder and White Matter Microstructure in the UK Biobank

Abstract: Our findings indicate that variation in the NETRIN1 signaling pathway may confer risk for major depressive disorder through effects on a number of white matter tracts.

Cited by 14 publications

References 40 publications

White Matter Microstructure and Its Relation to Longitudinal Measures of Depressive Symptoms in Mid- and Late Life

White Matter Microstructure and Its Relation to Longitudinal Measures of Depressive Symptoms in Mid- and Late Life

The Netrin-1/DCC guidance system: dopamine pathway maturation and psychiatric disorders emerging in adolescence

Expression quantitative trait loci-derived scores and white matter microstructure in UK Biobank: a novel approach to integrating genetics and neuroimaging

Contact Info

Product

Resources

About