Academic Journal
View in EDS

Genotype-stratified Default Mode Network hyperconnectivity in major depressive disorder: an MR imaging genetics study.

Bibliographic Details
Title: Genotype-stratified Default Mode Network hyperconnectivity in major depressive disorder: an MR imaging genetics study.
Authors: Singh P; Department of Radiodiagnosis, All India Institute of Medical Sciences Bathinda, Punjab, 151001, India., Singh S; Department of Radiodiagnosis, All India Institute of Medical Sciences Bathinda, Punjab, 151001, India., Peer S; Department of Radiodiagnosis, All India Institute of Medical Sciences Bathinda, Punjab, 151001, India., Ludhiadch A; Department of Community and Family Medicine, All India Institute of Medical Sciences Bathinda, Punjab, 151001, India., Singh J; Department of Psychiatry, All India Institute of Medical Sciences Bathinda, Punjab, 151001, India., Kaur H; Department of Radiodiagnosis, All India Institute of Medical Sciences Bathinda, Punjab, 151001, India., Munshi A; Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, Punjab, 151401, India. Electronic address: anjana.munshi@cup.edu.in.
Source: Journal of affective disorders [J Affect Disord] 2026 Aug 15; Vol. 407, pp. 121751. Date of Electronic Publication: 2026 Apr 07.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Elsevier/North-Holland Biomedical Press Country of Publication: Netherlands NLM ID: 7906073 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-2517 (Electronic) Linking ISSN: 01650327 NLM ISO Abbreviation: J Affect Disord Subsets: MEDLINE
Imprint Name(s): Original Publication: Amsterdam, Elsevier/North-Holland Biomedical Press.
MeSH Terms: Major Depressive Disorder*/genetics , Major Depressive Disorder*/physiopathology , Major Depressive Disorder*/diagnostic imaging , Tryptophan Hydroxylase*/genetics , Default Mode Network*/physiopathology , Default Mode Network*/diagnostic imaging , Brain*/physiopathology , Brain*/diagnostic imaging, Nerve Net/physiopathology ; Nerve Net/diagnostic imaging ; Humans ; Magnetic Resonance Imaging ; Female ; Male ; Adult ; Genotype ; Middle Aged ; Exome Sequencing
Abstract: Background: Major depressive disorder (MDD) is a prevalent and debilitating psychiatric condition defined by complex genetic and neurobiological underpinnings. The current study investigated the genetic variants associated with the disease and impact of significant variants on neurotransmitter pathways and their association with inherent brain connectivity patterns in MDD.
Methods: A total of 69 patients diagnosed with MDD were recruited. Whole-exome sequencing (WES) was carried out in 30 patients to identify relevant genetic variants. This was followed by the genotyping of two frequently observed variants in TPH1 (rs1799913) and DAOA (rs2391191) genes in additional 39 patients using Sanger Sequencing. All subjects participated in resting-state functional MRI (rs-fMRI), and genotype-connectivity associations were analysed using the CONN toolbox. Functional connectivity was evaluated within the Default Mode Network (DMN), and its associations with HAM-D scores and the incidence of depressive episodes were also examined.
Results: WES revealed variants in 21 genes involved in neurotransmission, synaptic plasticity, and intracellular signaling pathways. Individuals possessing altered TPH1 (rs1799913) and DAOA (rs2391191) genotypes demonstrated significantly increased connectivity within the DMN, particularly involving the posterior cingulate cortex, precuneus, dorsomedial prefrontal cortex, and subcalcarine gyrus. The heightened synchrony of the DMN exhibited a positive correlation with the severity of the Hamilton Depression Rating Scale and the occurrence of depressive episodes, suggesting a relationship between genotype, connectivity, and symptoms.
Conclusion: This study demonstrates that variations in TPH1 (rs1799913) and DAOA (rs2391191) genes are associated with atypical reinforcement of DMN connectivity in MDD. The findings support the role of serotonergic and glutamatergic pathways in maladaptive neural coupling and suggest that genotype-stratified DMN metrics may serve as intermediate neural phenotypes. Their status as disease-specific endophenotypes cannot be established in the absence of healthy or familial comparison groups. Further comprehensive, longitudinal research is essential to validate these results and evaluate their relevance for tailored interventions.
(Copyright © 2026 Elsevier B.V. All rights reserved.)
Competing Interests: Declaration of competing interest The authors declare that they possess no conflicts of interest, whether financial or otherwise.
Contributed Indexing: Keywords: DAOA; Default Mode Network; Functional connectivity; Imaging-genetics; Major depressive disorder; TPH1
Substance Nomenclature: EC 1.14.16.4 (Tryptophan Hydroxylase)
EC 1.14.16.4 (TPH1 protein, human)
Entry Date(s): Date Created: 20260409 Date Completed: 20260714 Latest Revision: 20260714
Update Code: 20260715
DOI: 10.1016/j.jad.2026.121751
PMID: 41956213
Database: MEDLINE
FullText Text:
  Availability: 0
CustomLinks:
  – Url: https://www.doi.org/10.1016/j.jad.2026.121751?
    Name: ScienceDirect (all content) (s7799221)
    Category: fullText
    Text: View record from ScienceDirect
    MouseOverText: View record from ScienceDirect
  – Url: https://resolver.ebsco.com/c/fiv2js/result?sid=EBSCO:cmedm&genre=article&issn=15732517&ISBN=&volume=407&issue=&date=20260815&spage=121751&pages=121751&title=Journal of affective disorders&atitle=Genotype-stratified%20Default%20Mode%20Network%20hyperconnectivity%20in%20major%20depressive%20disorder%3A%20an%20MR%20imaging%20genetics%20study.&aulast=Singh%20P&id=DOI:10.1016/j.jad.2026.121751
    Name: Full Text Finder (for New FTF UI) (ns324271)
    Category: fullText
    Text: Full Text Finder
    MouseOverText: Full Text Finder
Header DbId: cmedm
DbLabel: MEDLINE
An: 41956213
AccessLevel: 3
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 0
IllustrationInfo
Items – Name: Title
  Label: Title
  Group: Ti
  Data: Genotype-stratified Default Mode Network hyperconnectivity in major depressive disorder: an MR imaging genetics study.
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AU" term="%22Singh+P%22">Singh P</searchLink>; Department of Radiodiagnosis, All India Institute of Medical Sciences Bathinda, Punjab, 151001, India.<br /><searchLink fieldCode="AU" term="%22Singh+S%22">Singh S</searchLink>; Department of Radiodiagnosis, All India Institute of Medical Sciences Bathinda, Punjab, 151001, India.<br /><searchLink fieldCode="AU" term="%22Peer+S%22">Peer S</searchLink>; Department of Radiodiagnosis, All India Institute of Medical Sciences Bathinda, Punjab, 151001, India.<br /><searchLink fieldCode="AU" term="%22Ludhiadch+A%22">Ludhiadch A</searchLink>; Department of Community and Family Medicine, All India Institute of Medical Sciences Bathinda, Punjab, 151001, India.<br /><searchLink fieldCode="AU" term="%22Singh+J%22">Singh J</searchLink>; Department of Psychiatry, All India Institute of Medical Sciences Bathinda, Punjab, 151001, India.<br /><searchLink fieldCode="AU" term="%22Kaur+H%22">Kaur H</searchLink>; Department of Radiodiagnosis, All India Institute of Medical Sciences Bathinda, Punjab, 151001, India.<br /><searchLink fieldCode="AU" term="%22Munshi+A%22">Munshi A</searchLink>; Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, Punjab, 151401, India. Electronic address: anjana.munshi@cup.edu.in.
– Name: TitleSource
  Label: Source
  Group: Src
  Data: <searchLink fieldCode="JN" term="%227906073%22">Journal of affective disorders</searchLink> [J Affect Disord] 2026 Aug 15; Vol. 407, pp. 121751. <i>Date of Electronic Publication: </i>2026 Apr 07.
– Name: TypePub
  Label: Publication Type
  Group: TypPub
  Data: Journal Article
– Name: Language
  Label: Language
  Group: Lang
  Data: English
– Name: TitleSource
  Label: Journal Info
  Group: Src
  Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22Elsevier%2FNorth-Holland+Biomedical+Press%22">Elsevier/North-Holland Biomedical Press </searchLink><i>Country of Publication: </i>Netherlands <i>NLM ID: </i>7906073 <i>Publication Model: </i>Print-Electronic <i>Cited Medium: </i>Internet <i>ISSN: </i>1573-2517 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2201650327%22">01650327 </searchLink><i>NLM ISO Abbreviation: </i>J Affect Disord <i>Subsets: </i>MEDLINE
– Name: PublisherInfo
  Label: Imprint Name(s)
  Group: PubInfo
  Data: <i>Original Publication</i>: Amsterdam, Elsevier/North-Holland Biomedical Press.
– Name: SubjectMESH
  Label: MeSH Terms
  Group: Su
  Data: <searchLink fieldCode="MM" term="%22Major+Depressive+Disorder%22">Major Depressive Disorder*</searchLink>/<searchLink fieldCode="MM" term="%22Major+Depressive+Disorder+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Major+Depressive+Disorder%22">Major Depressive Disorder*</searchLink>/<searchLink fieldCode="MM" term="%22Major+Depressive+Disorder+physiopathology%22">physiopathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Major+Depressive+Disorder%22">Major Depressive Disorder*</searchLink>/<searchLink fieldCode="MM" term="%22Major+Depressive+Disorder+diagnostic+imaging%22">diagnostic imaging</searchLink> <br /><searchLink fieldCode="MM" term="%22Tryptophan+Hydroxylase%22">Tryptophan Hydroxylase*</searchLink>/<searchLink fieldCode="MM" term="%22Tryptophan+Hydroxylase+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Default+Mode+Network%22">Default Mode Network*</searchLink>/<searchLink fieldCode="MM" term="%22Default+Mode+Network+physiopathology%22">physiopathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Default+Mode+Network%22">Default Mode Network*</searchLink>/<searchLink fieldCode="MM" term="%22Default+Mode+Network+diagnostic+imaging%22">diagnostic imaging</searchLink> <br /><searchLink fieldCode="MM" term="%22Brain%22">Brain*</searchLink>/<searchLink fieldCode="MM" term="%22Brain+physiopathology%22">physiopathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Brain%22">Brain*</searchLink>/<searchLink fieldCode="MM" term="%22Brain+diagnostic+imaging%22">diagnostic imaging</searchLink><br /><searchLink fieldCode="MH" term="%22Nerve+Net%22">Nerve Net</searchLink>/<searchLink fieldCode="MH" term="%22Nerve+Net+physiopathology%22">physiopathology</searchLink> ; <searchLink fieldCode="MH" term="%22Nerve+Net%22">Nerve Net</searchLink>/<searchLink fieldCode="MH" term="%22Nerve+Net+diagnostic+imaging%22">diagnostic imaging</searchLink> ; <searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink> ; <searchLink fieldCode="MH" term="%22Magnetic+Resonance+Imaging%22">Magnetic Resonance Imaging</searchLink> ; <searchLink fieldCode="MH" term="%22Female%22">Female</searchLink> ; <searchLink fieldCode="MH" term="%22Male%22">Male</searchLink> ; <searchLink fieldCode="MH" term="%22Adult%22">Adult</searchLink> ; <searchLink fieldCode="MH" term="%22Genotype%22">Genotype</searchLink> ; <searchLink fieldCode="MH" term="%22Middle+Aged%22">Middle Aged</searchLink> ; <searchLink fieldCode="MH" term="%22Exome+Sequencing%22">Exome Sequencing</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Background: Major depressive disorder (MDD) is a prevalent and debilitating psychiatric condition defined by complex genetic and neurobiological underpinnings. The current study investigated the genetic variants associated with the disease and impact of significant variants on neurotransmitter pathways and their association with inherent brain connectivity patterns in MDD.<br />Methods: A total of 69 patients diagnosed with MDD were recruited. Whole-exome sequencing (WES) was carried out in 30 patients to identify relevant genetic variants. This was followed by the genotyping of two frequently observed variants in TPH1 (rs1799913) and DAOA (rs2391191) genes in additional 39 patients using Sanger Sequencing. All subjects participated in resting-state functional MRI (rs-fMRI), and genotype-connectivity associations were analysed using the CONN toolbox. Functional connectivity was evaluated within the Default Mode Network (DMN), and its associations with HAM-D scores and the incidence of depressive episodes were also examined.<br />Results: WES revealed variants in 21 genes involved in neurotransmission, synaptic plasticity, and intracellular signaling pathways. Individuals possessing altered TPH1 (rs1799913) and DAOA (rs2391191) genotypes demonstrated significantly increased connectivity within the DMN, particularly involving the posterior cingulate cortex, precuneus, dorsomedial prefrontal cortex, and subcalcarine gyrus. The heightened synchrony of the DMN exhibited a positive correlation with the severity of the Hamilton Depression Rating Scale and the occurrence of depressive episodes, suggesting a relationship between genotype, connectivity, and symptoms.<br />Conclusion: This study demonstrates that variations in TPH1 (rs1799913) and DAOA (rs2391191) genes are associated with atypical reinforcement of DMN connectivity in MDD. The findings support the role of serotonergic and glutamatergic pathways in maladaptive neural coupling and suggest that genotype-stratified DMN metrics may serve as intermediate neural phenotypes. Their status as disease-specific endophenotypes cannot be established in the absence of healthy or familial comparison groups. Further comprehensive, longitudinal research is essential to validate these results and evaluate their relevance for tailored interventions.<br /> (Copyright © 2026 Elsevier B.V. All rights reserved.)
– Name: Abstract
  Label: Competing Interests
  Group: Ab
  Data: Declaration of competing interest The authors declare that they possess no conflicts of interest, whether financial or otherwise.
– Name: SubjectMinor
  Label: Contributed Indexing
  Group:
  Data: <i>Keywords: </i>DAOA; Default Mode Network; Functional connectivity; Imaging-genetics; Major depressive disorder; TPH1
– Name: NumberCAS
  Label: Substance Nomenclature
  Group: ID
  Data: EC 1.14.16.4 (Tryptophan Hydroxylase)<br />EC 1.14.16.4 (TPH1 protein, human)
– Name: DateEntry
  Label: Entry Date(s)
  Group: Date
  Data: <i>Date Created: </i>20260409 <i>Date Completed: </i>20260714 <i>Latest Revision: </i>20260714
– Name: DateUpdate
  Label: Update Code
  Group: Date
  Data: 20260715
– Name: DOI
  Label: DOI
  Group: ID
  Data: 10.1016/j.jad.2026.121751
– Name: AN
  Label: PMID
  Group: ID
  Data: 41956213
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=cmedm&AN=41956213
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1016/j.jad.2026.121751
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        StartPage: 121751
    Subjects:
      – SubjectFull: Nerve Net physiopathology
        Type: general
      – SubjectFull: Nerve Net diagnostic imaging
        Type: general
      – SubjectFull: Humans
        Type: general
      – SubjectFull: Magnetic Resonance Imaging
        Type: general
      – SubjectFull: Female
        Type: general
      – SubjectFull: Male
        Type: general
      – SubjectFull: Adult
        Type: general
      – SubjectFull: Genotype
        Type: general
      – SubjectFull: Middle Aged
        Type: general
      – SubjectFull: Exome Sequencing
        Type: general
      – SubjectFull: Major Depressive Disorder genetics
        Type: general
      – SubjectFull: Major Depressive Disorder physiopathology
        Type: general
      – SubjectFull: Major Depressive Disorder diagnostic imaging
        Type: general
      – SubjectFull: Tryptophan Hydroxylase genetics
        Type: general
      – SubjectFull: Default Mode Network physiopathology
        Type: general
      – SubjectFull: Default Mode Network diagnostic imaging
        Type: general
      – SubjectFull: Brain physiopathology
        Type: general
      – SubjectFull: Brain diagnostic imaging
        Type: general
    Titles:
      – TitleFull: Genotype-stratified Default Mode Network hyperconnectivity in major depressive disorder: an MR imaging genetics study.
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Singh P
      – PersonEntity:
          Name:
            NameFull: Singh S
      – PersonEntity:
          Name:
            NameFull: Peer S
      – PersonEntity:
          Name:
            NameFull: Ludhiadch A
      – PersonEntity:
          Name:
            NameFull: Singh J
      – PersonEntity:
          Name:
            NameFull: Kaur H
      – PersonEntity:
          Name:
            NameFull: Munshi A
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 15
              M: 08
              Text: 2026 Aug 15
              Type: published
              Y: 2026
          Identifiers:
            – Type: issn-electronic
              Value: 1573-2517
          Numbering:
            – Type: volume
              Value: 407
          Titles:
            – TitleFull: Journal of affective disorders
              Type: main
ResultId 1