Using Clinical Characteristics to Identify Which Patients With Major Depressive Disorder Have a Higher Genetic Load for Three Psychiatric Disorders

Judith Verduijn, Yuri Milaneschi, Wouter J. Peyrot, Jouke Jan Hottenga, Abdel Abdellaoui, Eco J.C. de Geus, Johannes H. Smit, Gerome Breen, Cathryn M. Lewis, Dorret I. Boomsma, Aartjan T.F. Beekman, Brenda W.J.H. Penninx

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background Limited successes of gene finding for major depressive disorder (MDD) may be partly due to phenotypic heterogeneity. We tested whether the genetic load for MDD, bipolar disorder, and schizophrenia (SCZ) is increased in phenotypically more homogenous MDD patients identified by specific clinical characteristics. Methods Patients (n = 1539) with a DSM-IV MDD diagnosis and control subjects (n = 1792) were from two large cohort studies (Netherlands Study of Depression and Anxiety and Netherlands Twin Register). Genomic profile risk scores (GPRSs) for MDD, bipolar disorder, and SCZ were based on meta-analysis results of the Psychiatric Genomics Consortium. Regression analyses (adjusted for year of birth, sex, three principal components) examined the association between GPRSs with characteristics and GPRSs with MDD subgroups stratified according to the most relevant characteristics. The proportion of liability variance explained by GPRSs for each MDD subgroup was estimated. Results GPRS-MDD explained 1.0% (p = 4.19e−09) of MDD variance, and 1.5% (p = 4.23e−09) for MDD endorsing nine DSM symptoms. GPRS–bipolar disorder explained 0.6% (p = 2.97e−05) of MDD variance and 1.1% (p = 1.30e−05) for MDD with age at onset <18 years. GPRS-SCZ explained 2.0% (p = 6.15e−16) of MDD variance, 2.6% (p = 2.88e−10) for MDD with higher symptom severity, and 2.3% (p = 2.26e−13) for MDD endorsing nine DSM symptoms. An independent sample replicated the same pattern of stronger associations between cases with more DSM symptoms, as compared to overall MDD, and GPRS-SCZ. Conclusions MDD patients with early age at onset and higher symptom severity have an increased genetic risk for three major psychiatric disorders, suggesting that it is useful to create phenotypically more homogenous groups when searching for genes associated with MDD.

Original languageEnglish
Pages (from-to)316-324
Number of pages9
JournalBiological Psychiatry
Volume81
Issue number4
DOIs
Publication statusPublished - 15 Feb 2017

Cite this

@article{4d2c0d74be3749dc9ef9578d65acb5cd,
title = "Using Clinical Characteristics to Identify Which Patients With Major Depressive Disorder Have a Higher Genetic Load for Three Psychiatric Disorders",
abstract = "Background Limited successes of gene finding for major depressive disorder (MDD) may be partly due to phenotypic heterogeneity. We tested whether the genetic load for MDD, bipolar disorder, and schizophrenia (SCZ) is increased in phenotypically more homogenous MDD patients identified by specific clinical characteristics. Methods Patients (n = 1539) with a DSM-IV MDD diagnosis and control subjects (n = 1792) were from two large cohort studies (Netherlands Study of Depression and Anxiety and Netherlands Twin Register). Genomic profile risk scores (GPRSs) for MDD, bipolar disorder, and SCZ were based on meta-analysis results of the Psychiatric Genomics Consortium. Regression analyses (adjusted for year of birth, sex, three principal components) examined the association between GPRSs with characteristics and GPRSs with MDD subgroups stratified according to the most relevant characteristics. The proportion of liability variance explained by GPRSs for each MDD subgroup was estimated. Results GPRS-MDD explained 1.0{\%} (p = 4.19e−09) of MDD variance, and 1.5{\%} (p = 4.23e−09) for MDD endorsing nine DSM symptoms. GPRS–bipolar disorder explained 0.6{\%} (p = 2.97e−05) of MDD variance and 1.1{\%} (p = 1.30e−05) for MDD with age at onset <18 years. GPRS-SCZ explained 2.0{\%} (p = 6.15e−16) of MDD variance, 2.6{\%} (p = 2.88e−10) for MDD with higher symptom severity, and 2.3{\%} (p = 2.26e−13) for MDD endorsing nine DSM symptoms. An independent sample replicated the same pattern of stronger associations between cases with more DSM symptoms, as compared to overall MDD, and GPRS-SCZ. Conclusions MDD patients with early age at onset and higher symptom severity have an increased genetic risk for three major psychiatric disorders, suggesting that it is useful to create phenotypically more homogenous groups when searching for genes associated with MDD.",
keywords = "Clinical characteristics, Genetic load, Genetics, Heterogeneity, Major depressive disorder, Replication, Staging",
author = "Judith Verduijn and Yuri Milaneschi and Peyrot, {Wouter J.} and Hottenga, {Jouke Jan} and Abdel Abdellaoui and {de Geus}, {Eco J.C.} and Smit, {Johannes H.} and Gerome Breen and Lewis, {Cathryn M.} and Boomsma, {Dorret I.} and Beekman, {Aartjan T.F.} and Penninx, {Brenda W.J.H.}",
year = "2017",
month = "2",
day = "15",
doi = "10.1016/j.biopsych.2016.05.024",
language = "English",
volume = "81",
pages = "316--324",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "4",

}

Using Clinical Characteristics to Identify Which Patients With Major Depressive Disorder Have a Higher Genetic Load for Three Psychiatric Disorders. / Verduijn, Judith; Milaneschi, Yuri; Peyrot, Wouter J.; Hottenga, Jouke Jan; Abdellaoui, Abdel; de Geus, Eco J.C.; Smit, Johannes H.; Breen, Gerome; Lewis, Cathryn M.; Boomsma, Dorret I.; Beekman, Aartjan T.F.; Penninx, Brenda W.J.H.

In: Biological Psychiatry, Vol. 81, No. 4, 15.02.2017, p. 316-324.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Using Clinical Characteristics to Identify Which Patients With Major Depressive Disorder Have a Higher Genetic Load for Three Psychiatric Disorders

AU - Verduijn, Judith

AU - Milaneschi, Yuri

AU - Peyrot, Wouter J.

AU - Hottenga, Jouke Jan

AU - Abdellaoui, Abdel

AU - de Geus, Eco J.C.

AU - Smit, Johannes H.

AU - Breen, Gerome

AU - Lewis, Cathryn M.

AU - Boomsma, Dorret I.

AU - Beekman, Aartjan T.F.

AU - Penninx, Brenda W.J.H.

PY - 2017/2/15

Y1 - 2017/2/15

N2 - Background Limited successes of gene finding for major depressive disorder (MDD) may be partly due to phenotypic heterogeneity. We tested whether the genetic load for MDD, bipolar disorder, and schizophrenia (SCZ) is increased in phenotypically more homogenous MDD patients identified by specific clinical characteristics. Methods Patients (n = 1539) with a DSM-IV MDD diagnosis and control subjects (n = 1792) were from two large cohort studies (Netherlands Study of Depression and Anxiety and Netherlands Twin Register). Genomic profile risk scores (GPRSs) for MDD, bipolar disorder, and SCZ were based on meta-analysis results of the Psychiatric Genomics Consortium. Regression analyses (adjusted for year of birth, sex, three principal components) examined the association between GPRSs with characteristics and GPRSs with MDD subgroups stratified according to the most relevant characteristics. The proportion of liability variance explained by GPRSs for each MDD subgroup was estimated. Results GPRS-MDD explained 1.0% (p = 4.19e−09) of MDD variance, and 1.5% (p = 4.23e−09) for MDD endorsing nine DSM symptoms. GPRS–bipolar disorder explained 0.6% (p = 2.97e−05) of MDD variance and 1.1% (p = 1.30e−05) for MDD with age at onset <18 years. GPRS-SCZ explained 2.0% (p = 6.15e−16) of MDD variance, 2.6% (p = 2.88e−10) for MDD with higher symptom severity, and 2.3% (p = 2.26e−13) for MDD endorsing nine DSM symptoms. An independent sample replicated the same pattern of stronger associations between cases with more DSM symptoms, as compared to overall MDD, and GPRS-SCZ. Conclusions MDD patients with early age at onset and higher symptom severity have an increased genetic risk for three major psychiatric disorders, suggesting that it is useful to create phenotypically more homogenous groups when searching for genes associated with MDD.

AB - Background Limited successes of gene finding for major depressive disorder (MDD) may be partly due to phenotypic heterogeneity. We tested whether the genetic load for MDD, bipolar disorder, and schizophrenia (SCZ) is increased in phenotypically more homogenous MDD patients identified by specific clinical characteristics. Methods Patients (n = 1539) with a DSM-IV MDD diagnosis and control subjects (n = 1792) were from two large cohort studies (Netherlands Study of Depression and Anxiety and Netherlands Twin Register). Genomic profile risk scores (GPRSs) for MDD, bipolar disorder, and SCZ were based on meta-analysis results of the Psychiatric Genomics Consortium. Regression analyses (adjusted for year of birth, sex, three principal components) examined the association between GPRSs with characteristics and GPRSs with MDD subgroups stratified according to the most relevant characteristics. The proportion of liability variance explained by GPRSs for each MDD subgroup was estimated. Results GPRS-MDD explained 1.0% (p = 4.19e−09) of MDD variance, and 1.5% (p = 4.23e−09) for MDD endorsing nine DSM symptoms. GPRS–bipolar disorder explained 0.6% (p = 2.97e−05) of MDD variance and 1.1% (p = 1.30e−05) for MDD with age at onset <18 years. GPRS-SCZ explained 2.0% (p = 6.15e−16) of MDD variance, 2.6% (p = 2.88e−10) for MDD with higher symptom severity, and 2.3% (p = 2.26e−13) for MDD endorsing nine DSM symptoms. An independent sample replicated the same pattern of stronger associations between cases with more DSM symptoms, as compared to overall MDD, and GPRS-SCZ. Conclusions MDD patients with early age at onset and higher symptom severity have an increased genetic risk for three major psychiatric disorders, suggesting that it is useful to create phenotypically more homogenous groups when searching for genes associated with MDD.

KW - Clinical characteristics

KW - Genetic load

KW - Genetics

KW - Heterogeneity

KW - Major depressive disorder

KW - Replication

KW - Staging

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U2 - 10.1016/j.biopsych.2016.05.024

DO - 10.1016/j.biopsych.2016.05.024

M3 - Article

VL - 81

SP - 316

EP - 324

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 4

ER -