Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis
Vipavee Niemsiri
(1)
,
Sara Brin Rosenthal
(2, 1)
,
Caroline M Nievergelt
(1)
,
Adam X Maihofer
(1)
,
Maria C Marchetto
(1, 3)
,
Renata Santos
(3, 4)
,
Tatyana Shekhtman
(1)
,
Ney Alliey-Rodriguez
(5, 6)
,
Amit Anand
(7, 8, 9)
,
Yokesh Balaraman
(10)
,
Wade H Berrettini
(11)
,
Holli Bertram
(12)
,
Katherine E Burdick
(9, 8)
,
Joseph R Calabrese
(13, 14)
,
Cynthia V Calkin
(15)
,
Carla Conroy
(13, 14)
,
William H Coryell
(16)
,
Anna Demodena
(17)
,
Lisa T Eyler
(1)
,
Scott Feeder
(18)
,
Carrie Fisher
(10)
,
Nicole Frazier
(12)
,
Mark A Frye
(18)
,
Keming Gao
(13, 14)
,
Julie Garnham
(15)
,
Elliot S Gershon
(5)
,
Fernando S Goes
(19)
,
Toyomi Goto
(14)
,
Gloria J Harrington
(12)
,
Petter Jakobsen
(20, 21)
,
Masoud Kamali
(22, 8, 12)
,
Marisa Kelly
(12)
,
Susan G Leckband
(17)
,
Falk W Lohoff
(11)
,
Michael J Mccarthy
(23)
,
Melvin G Mcinnis
(12)
,
David Craig
(24)
,
Caitlin E Millett
(9, 8)
,
Francis Mondimore
(19)
,
Gunnar Morken
(25, 26)
,
John I Nurnberger
(10, 27)
,
Claire Donovan
(15)
,
Ketil J Øedegaard
(20, 21)
,
Kelly Ryan
(12)
,
Martha Schinagle
(14)
,
Paul D Shilling
(28)
,
Claire Slaney
(15)
,
Emma K Stapp
(29, 19)
,
Andrea Stautland
(21)
,
Bruce Tarwater
(16)
,
Peter P Zandi
(19)
,
Martin Alda
(15, 30)
,
Kathleen M Fisch
(1, 31)
,
Fred H Gage
(3)
,
John R Kelsoe
(1, 32)
1
UC San Diego -
University of California [San Diego]
2 CCBB - Center for Computational Biology and Bioinformatics [San Diego, USA]
3 The Salk Institute for Biological Studies
4 IPNP - U1266 Inserm - Institut de psychiatrie et neurosciences de Paris
5 University of Chicago
6 Northwestern University [Chicago, Ill. USA]
7 Massachusetts General Hospital [Boston]
8 HMS - Harvard Medical School [Boston]
9 Brigham and Women’s Hospital [Boston, MA]
10 Indiana University School of Medicine
11 University of Pennsylvania
12 University of Michigan [Ann Arbor]
13 UH Cleveland Medical Center - University Hospitals Case Medical Center
14 Case Western Reserve University [Cleveland]
15 Dalhousie University [Halifax]
16 University of Iowa [Iowa City]
17 VASDHS - VA San Diego Healthcare System [San Diego, CA, USA]
18 Mayo Clinic [Rochester]
19 JHU - Johns Hopkins University
20 Haukeland University Hospital
21 UiB - University of Bergen
22 Massachusetts General Hospital [Boston, MA, USA]
23 UC - University of California
24 USC - University of Southern California
25 St. Olav's University Hospital - St. Olavs Hospital HF
26 NTNU - Norwegian University of Science and Technology
27 Stark Neurosciences Research Institute
28 UC San Francisco - University of California [San Francisco]
29 Johns Hopkins Bloomberg School of Public Health [Baltimore]
30 NIMH - National Institute of Mental Health [Klecany, Czech Republic]
31 Center for Computational Biology and Bioinformatics
32 IFGM - INSTITUTE FOR GENOMIC MEDICINE [ San Diego, USA]
2 CCBB - Center for Computational Biology and Bioinformatics [San Diego, USA]
3 The Salk Institute for Biological Studies
4 IPNP - U1266 Inserm - Institut de psychiatrie et neurosciences de Paris
5 University of Chicago
6 Northwestern University [Chicago, Ill. USA]
7 Massachusetts General Hospital [Boston]
8 HMS - Harvard Medical School [Boston]
9 Brigham and Women’s Hospital [Boston, MA]
10 Indiana University School of Medicine
11 University of Pennsylvania
12 University of Michigan [Ann Arbor]
13 UH Cleveland Medical Center - University Hospitals Case Medical Center
14 Case Western Reserve University [Cleveland]
15 Dalhousie University [Halifax]
16 University of Iowa [Iowa City]
17 VASDHS - VA San Diego Healthcare System [San Diego, CA, USA]
18 Mayo Clinic [Rochester]
19 JHU - Johns Hopkins University
20 Haukeland University Hospital
21 UiB - University of Bergen
22 Massachusetts General Hospital [Boston, MA, USA]
23 UC - University of California
24 USC - University of Southern California
25 St. Olav's University Hospital - St. Olavs Hospital HF
26 NTNU - Norwegian University of Science and Technology
27 Stark Neurosciences Research Institute
28 UC San Francisco - University of California [San Francisco]
29 Johns Hopkins Bloomberg School of Public Health [Baltimore]
30 NIMH - National Institute of Mental Health [Klecany, Czech Republic]
31 Center for Computational Biology and Bioinformatics
32 IFGM - INSTITUTE FOR GENOMIC MEDICINE [ San Diego, USA]
Caroline M Nievergelt
- Fonction : Auteur
- PersonId : 805590
- ORCID : 0000-0001-5766-8923
Renata Santos
- Fonction : Auteur
- PersonId : 179805
- IdHAL : renata-santos
- ORCID : 0000-0002-3085-5128
Ney Alliey-Rodriguez
- Fonction : Auteur
- PersonId : 1259650
- ORCID : 0000-0001-8594-5676
Cynthia V Calkin
- Fonction : Auteur
- PersonId : 1259651
- ORCID : 0000-0003-4673-3990
Julie Garnham
- Fonction : Auteur
- PersonId : 769346
- ORCID : 0000-0002-7987-4995
Fernando S Goes
- Fonction : Auteur
- PersonId : 1248690
- ORCID : 0000-0001-6262-8264
Masoud Kamali
- Fonction : Auteur
- PersonId : 1259652
- ORCID : 0000-0003-1453-5201
Marisa Kelly
- Fonction : Auteur
- PersonId : 1259653
- ORCID : 0000-0002-7151-1938
Falk W Lohoff
- Fonction : Auteur
- PersonId : 1259654
- ORCID : 0000-0002-0480-7755
Melvin G Mcinnis
- Fonction : Auteur
- PersonId : 1259655
- ORCID : 0000-0002-0375-6247
Gunnar Morken
- Fonction : Auteur
Paul D Shilling
- Fonction : Auteur
- PersonId : 805592
- ORCID : 0000-0002-0129-5504
Emma K Stapp
- Fonction : Auteur
- PersonId : 1259656
- ORCID : 0000-0003-0628-0704
Andrea Stautland
- Fonction : Auteur
- PersonId : 1259657
- ORCID : 0000-0002-6595-3692
Martin Alda
- Fonction : Auteur
- PersonId : 804017
- ORCID : 0000-0001-9544-3944
Fred H Gage
- Fonction : Auteur
- PersonId : 1259658
- ORCID : 0000-0002-0938-4106
John R Kelsoe
- Fonction : Auteur
- PersonId : 1259659
Résumé
Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500-and top 2000-proximal gene networks and the GWAB gene list (P hypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.
Domaines
Neurosciences [q-bio.NC]Origine | Publication financée par une institution |
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Licence |