Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia

Shashwath A. Meda, Gualberto Ruaño, Andreas Windemuth, Kasey O'Neil, Clifton Berwise, Sabra M. Dunn, Leah E. Boccaccio, Balaji Narayanan, Mohan Kocherla, Emma Sprooten, Matcheri S. Keshavan, Carol A. Tamminga, John A. Sweeney, Brett A. Clementz, Vince D. Calhoun, Godfrey D. Pearlson

Research output: Contribution to journalArticle

114 Citations (Scopus)

Abstract

The brain's default mode network (DMN) is highly heritable and is compromised in a variety of psychiatric disorders. However, genetic control over the DMN in schizophrenia (SZ) and psychotic bipolar disorder (PBP) is largely unknown. Study subjects (n = 1,305) underwent a resting-state functional MRI scan and were analyzed by a two-stage approach. The initial analysis used independent component analysis (ICA) in 324 healthy controls, 296 SZ probands, 300 PBP probands, 179 unaffected first-degree relatives of SZ probands (SZREL), and 206 unaffected first-degree relatives of PBP probands to identify DMNs and to test their biomarker and/or endophenotype status. A subset of controls and probands (n = 549) then was subjected to a parallel ICA (para-ICA) to identify imaging-genetic relationships. ICA identified three DMNs. Hypoconnectivity was observed in both patient groups in all DMNs. Similar patterns observed in SZREL were restricted to only one network. DMN connectivity also correlated with several symptom measures. Para-ICA identified five sub-DMNs that were significantly associated with five different genetic networks. Several top-ranking SNPs across these networks belonged to previously identified, well-known psychosis/mood disorder genes. Global enrichment analyses revealed processes including NMDA-related long-term potentiation, PKA, immune response signaling, axon guidance, and synaptogenesis that significantly influenced DMN modulation in psychoses. In summary, we observed both unique and shared impairments in functional connectivity across the SZ and PBP cohorts; these impairments were selectively familial only for SZREL. Genes regulating specific neurodevelopment/transmission processes primarily mediated DMN disconnectivity. The study thus identifies biological pathways related to a widely researched quantitative trait that might suggest novel, targeted drug treatments for these diseases.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number19
DOIs
StatePublished - May 13 2014

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Bipolar Disorder
Psychotic Disorders
Schizophrenia
Multivariate Analysis
Magnetic Resonance Imaging
Endophenotypes
Long-Term Potentiation
N-Methylaspartate
Mood Disorders
Genes
Single Nucleotide Polymorphism
Psychiatry
Biomarkers
Brain
Pharmaceutical Preparations

Keywords

  • Architecture
  • BSNIP
  • Genetics
  • Molecular

ASJC Scopus subject areas

  • General

Cite this

Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia. / Meda, Shashwath A.; Ruaño, Gualberto; Windemuth, Andreas; O'Neil, Kasey; Berwise, Clifton; Dunn, Sabra M.; Boccaccio, Leah E.; Narayanan, Balaji; Kocherla, Mohan; Sprooten, Emma; Keshavan, Matcheri S.; Tamminga, Carol A.; Sweeney, John A.; Clementz, Brett A.; Calhoun, Vince D.; Pearlson, Godfrey D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 19, 13.05.2014.

Research output: Contribution to journalArticle

Meda, SA, Ruaño, G, Windemuth, A, O'Neil, K, Berwise, C, Dunn, SM, Boccaccio, LE, Narayanan, B, Kocherla, M, Sprooten, E, Keshavan, MS, Tamminga, CA, Sweeney, JA, Clementz, BA, Calhoun, VD & Pearlson, GD 2014, 'Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 19. https://doi.org/10.1073/pnas.1313093111
Meda, Shashwath A. ; Ruaño, Gualberto ; Windemuth, Andreas ; O'Neil, Kasey ; Berwise, Clifton ; Dunn, Sabra M. ; Boccaccio, Leah E. ; Narayanan, Balaji ; Kocherla, Mohan ; Sprooten, Emma ; Keshavan, Matcheri S. ; Tamminga, Carol A. ; Sweeney, John A. ; Clementz, Brett A. ; Calhoun, Vince D. ; Pearlson, Godfrey D. / Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 19.
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