title: A Combined Pathway and Regional Heritability Analysis Indicates NETRIN1 Pathway Is Associated With Major Depressive Disorder.
abstract: Genome-wide association studies (GWASs) of major depressive disorder (MDD) have identified few significant associations. Testing the aggregation of genetic variants, in particular biological pathways, may be more powerful. Regional heritability analysis can be used to detect genomic regions that contribute to disease risk.
  
  
  
  We integrated pathway analysis and multilevel regional heritability analyses in a pipeline designed to identify MDD-associated pathways. The pipeline was applied to two independent GWAS samples [Generation Scotland: The Scottish Family Health Study (GS:SFHS, N = 6455) and Psychiatric Genomics Consortium (PGC:MDD) (N = 18,759)]. A polygenic risk score (PRS) composed of single nucleotide polymorphisms from the pathway most consistently associated with MDD was created, and its accuracy to predict MDD, using area under the curve, logistic regression, and linear mixed model analyses, was tested.
  
  
  
  In GS:SFHS, four pathways were significantly associated with MDD, and two of these explained a significant amount of pathway-level regional heritability. In PGC:MDD, one pathway was significantly associated with MDD. Pathway-level regional heritability was significant in this pathway in one subset of PGC:MDD. For both samples the regional heritabilities were further localized to the gene and subregion levels. The NETRIN1 signaling pathway showed the most consistent association with MDD across the two samples. PRSs from this pathway showed competitive predictive accuracy compared with the whole-genome PRSs when using area under the curve statistics, logistic regression, and linear mixed model.
  
  
  
  These post-GWAS analyses highlight the value of combining multiple methods on multiple GWAS data for the identification of risk pathways for MDD. The NETRIN1 signaling pathway is identified as a candidate pathway for MDD and should be explored in further large population studies.
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom. Electronic address: y.zeng-6@sms.ed.ac.uk.
authors.forename: Yanni
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: MRC Human Genetics Unit, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Pau
authors.initials: P
authors.lastname: Navarro
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Fernandez-Pujals
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Lynsey S
authors.initials: LS
authors.lastname: Hall
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Toni-Kim
authors.initials: TK
authors.lastname: Clarke
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom; Medical Genetics Section, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Pippa A
authors.initials: PA
authors.lastname: Thomson
authors.affiliation: Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom; Division of Population Health Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Blair H
authors.initials: BH
authors.lastname: Smith
authors.affiliation: Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom; Division of Applied Health Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Lynne J
authors.initials: LJ
authors.lastname: Hocking
authors.affiliation: Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom; Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Sandosh
authors.initials: S
authors.lastname: Padmanabhan
authors.affiliation: MRC Human Genetics Unit, University of Edinburgh, Edinburgh, United Kingdom; Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: MacIntyre
authors.affiliation: Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Wray
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom; Generation Scotland, University of Edinburgh, Edinburgh, United Kingdom; Institute of Genetics and Molecular Medicine, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom; Medical Genetics Section, University of Edinburgh, Edinburgh, United Kingdom; Generation Scotland, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.affiliation: MRC Human Genetics Unit, University of Edinburgh, Edinburgh, United Kingdom; The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Chris S
authors.initials: CS
authors.lastname: Haley
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom; Generation Scotland, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: McIntosh
mesh_terms: D000328:Adult; D003865:Major Depressive Disorder / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance; D009414:Nerve Growth Factors / Q000235:genetics*; D000075388:Netrin-1; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1
keywords: DCC; MDD; NETRIN1; Pathway analysis; Polygenic risk score; Regional heritability