Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia.
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. Hypo-connectivity 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.
Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, Hartford, CT 06102; shashwath.meda@hhchealth.org.
Shashwath A
SA
Meda
Genomas Inc., Hartford, CT 06102;Genetics Research Center, Hartford Hospital, Hartford, CT 06102;
Gualberto
G
Ruaño
Genomas Inc., Hartford, CT 06102;
Andreas
A
Windemuth
Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, Hartford, CT 06102;
Kasey
K
O'Neil
Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, Hartford, CT 06102;
Clifton
C
Berwise
Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, Hartford, CT 06102;
Sabra M
SM
Dunn
Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, Hartford, CT 06102;
Leah E
LE
Boccaccio
Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, Hartford, CT 06102;
Balaji
B
Narayanan
Genomas Inc., Hartford, CT 06102;
Mohan
M
Kocherla
Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, Hartford, CT 06102;
Emma
E
Sprooten
Department of Psychiatry, Beth Israel Deaconess Hospital, Harvard Medical School, Boston, MA 02215;
Matcheri S
MS
Keshavan
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390;
Carol A
CA
Tamminga
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390;
John A
JA
Sweeney
Department of Psychology, University of Georgia, Athens, GA 30602;
Brett A
BA
Clementz
The Mind Research Network, Albuquerque, NM 87106;Departments of Psychiatry andDepartment of Electrical and Computer Engineering, The University of New Mexico, Albuquerque, NM 87106.
Vince D
VD
Calhoun
Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, Hartford, CT 06102;Departments of Psychiatry andNeurobiology, Yale University, New Haven, CT 06520; and.
Godfrey D
GD
Pearlson
D000328:Adult; D001714:Bipolar Disorder / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D001921:Brain / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009415:Nerve Net; D012146:Rest / Q000502:physiology; D012307:Risk Factors; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D055815:Young Adult
BSNIP; architecture; genetics; molecular