title: Polygenic dissection of major depression clinical heterogeneity.
abstract: The molecular mechanisms underlying major depressive disorder (MDD) are largely unknown. Limited success of previous genetics studies may be attributable to heterogeneity of MDD, aggregating biologically different subtypes. We examined the polygenic features of MDD and two common clinical subtypes (typical and atypical) defined by symptom profiles in a large sample of adults with established diagnoses. Data were from 1530 patients of the Netherlands Study of Depression and Anxiety (NESDA) and 1700 controls mainly from the Netherlands Twin Register (NTR). Diagnoses of MDD and its subtypes were based on DSM-IV symptoms. Genetic overlap of MDD and subtypes with psychiatric (MDD, bipolar disorder, schizophrenia) and metabolic (body mass index (BMI), C-reactive protein, triglycerides) traits was evaluated via genomic profile risk scores (GPRS) generated from meta-analysis results of large international consortia. Single nucleotide polymorphism (SNP)-heritability of MDD and subtypes was also estimated. MDD was associated with psychiatric GPRS, while no association was found for GPRS of metabolic traits. MDD subtypes had differential polygenic signatures: typical was strongly associated with schizophrenia GPRS (odds ratio (OR)=1.54, P=7.8e-9), while atypical was additionally associated with BMI (OR=1.29, P=2.7e-4) and triglycerides (OR=1.21, P=0.006) GPRS. Similar results were found when only the highly discriminatory symptoms of appetite/weight were used to define subtypes. SNP-heritability was 32% for MDD, 38% and 43% for subtypes with, respectively, decreased (typical) and increased (atypical) appetite/weight. In conclusion, MDD subtypes are characterized by partially distinct polygenic liabilities and may represent more homogeneous phenotypes. Disentangling MDD heterogeneity may help the psychiatric field moving forward in the search for molecular roots of depression.
authors.affiliation: Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
authors.forename: Y
authors.initials: Y
authors.lastname: Milaneschi
authors.affiliation: Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Lamers
authors.affiliation: Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
authors.forename: W J
authors.initials: WJ
authors.lastname: Peyrot
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Abdellaoui
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Willemsen
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: J-J
authors.initials: JJ
authors.lastname: Hottenga
authors.affiliation: Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Jansen
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Mbarek
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Dehghan
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: D I
authors.initials: DI
authors.lastname: Boomsma
authors.affiliation: Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
authors.forename: B W J H
authors.initials: BW
authors.lastname: Penninx
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics / Q000378:metabolism; D015992:Body Mass Index; D002097:C-Reactive Protein / Q000378:metabolism; D003865:Major Depressive Disorder / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D020412:Multifactorial Inheritance / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014280:Triglycerides / Q000378:metabolism
chemical_list: D014280:Triglycerides; D002097:C-Reactive Protein