Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis

Vipavee Niemsiri; Sara Brin Rosenthal; Caroline M. Nievergelt; Adam X. Maihofer; Maria C. Marchetto; Renata Santos; Tatyana Shekhtman; Ney Alliey-Rodriguez; Amit Anand; Yokesh Balaraman; Wade H. Berrettini; Holli Bertram; Katherine E. Burdick; Joseph R. Calabrese; Cynthia V. Calkin; Carla Conroy; William H. Coryell; Anna DeModena; Lisa T. Eyler; Scott Feeder; Carrie Fisher; Nicole Frazier; Mark A. Frye; Keming Gao; Julie Garnham; Elliot S. Gershon; Fernando S. Goes; Toyomi Goto; Gloria J. Harrington; Petter Jakobsen; Masoud Kamali; Marisa Kelly; Susan G. Leckband; Falk W. Lohoff; Michael J. McCarthy; Melvin G. McInnis; David Craig; Caitlin E. Millett; Francis Mondimore; Gunnar Morken; John I. Nurnberger; Claire O’ Donovan; Ketil J. Øedegaard; Kelly Ryan; Martha Schinagle; Paul D. Shilling; Claire Slaney; Emma K. Stapp; Andrea Stautland; Bruce Tarwater; Peter P. Zandi; Martin Alda; Kathleen M. Fisch; Fred H. Gage; John R. Kelsoe

doi:10.1038/s41380-022-01909-9

Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis

Vipavee Niemsiri, Sara Brin Rosenthal, Caroline M. Nievergelt, Adam X. Maihofer, Maria C. Marchetto, Renata Santos, Tatyana Shekhtman, Ney Alliey-Rodriguez, Amit Anand, Yokesh Balaraman, Wade H. Berrettini, Holli Bertram, Katherine E. Burdick, Joseph R. Calabrese, Cynthia V. Calkin, Carla Conroy, William H. Coryell, Anna DeModena, Lisa T. Eyler, Scott FeederCarrie Fisher, Nicole Frazier, Mark A. Frye, Keming Gao, Julie Garnham, Elliot S. Gershon, Fernando S. Goes, Toyomi Goto, Gloria J. Harrington, Petter Jakobsen, Masoud Kamali, Marisa Kelly, Susan G. Leckband, Falk W. Lohoff, Michael J. McCarthy, Melvin G. McInnis, David Craig, Caitlin E. Millett, Francis Mondimore, Gunnar Morken, John I. Nurnberger, Claire O’ Donovan, Ketil J. Øedegaard, Kelly Ryan, Martha Schinagle, Paul D. Shilling, Claire Slaney, Emma K. Stapp, Andrea Stautland, Bruce Tarwater, Peter P. Zandi, Martin Alda, Kathleen M. Fisch, Fred H. Gage, John R. Kelsoe

Psychiatry and Psychology

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Journal	Molecular Psychiatry
DOIs	https://doi.org/10.1038/s41380-022-01909-9
State	Accepted/In press - 2023

ASJC Scopus subject areas

Molecular Biology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

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10.1038/s41380-022-01909-9

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Niemsiri, V., Rosenthal, S. B., Nievergelt, C. M., Maihofer, A. X., Marchetto, M. C., Santos, R., Shekhtman, T., Alliey-Rodriguez, N., Anand, A., Balaraman, Y., Berrettini, W. H., Bertram, H., Burdick, K. E., Calabrese, J. R., Calkin, C. V., Conroy, C., Coryell, W. H., DeModena, A., Eyler, L. T., ... Kelsoe, J. R. (Accepted/In press). Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis. Molecular Psychiatry. https://doi.org/10.1038/s41380-022-01909-9

Niemsiri, V, Rosenthal, SB, Nievergelt, CM, Maihofer, AX, Marchetto, MC, Santos, R, Shekhtman, T, Alliey-Rodriguez, N, Anand, A, Balaraman, Y, Berrettini, WH, Bertram, H, Burdick, KE, Calabrese, JR, Calkin, CV, Conroy, C, Coryell, WH, DeModena, A, Eyler, LT, Feeder, S, Fisher, C, Frazier, N, Frye, MA, Gao, K, Garnham, J, Gershon, ES, Goes, FS, Goto, T, Harrington, GJ, Jakobsen, P, Kamali, M, Kelly, M, Leckband, SG, Lohoff, FW, McCarthy, MJ, McInnis, MG, Craig, D, Millett, CE, Mondimore, F, Morken, G, Nurnberger, JI, Donovan, CO, Øedegaard, KJ, Ryan, K, Schinagle, M, Shilling, PD, Slaney, C, Stapp, EK, Stautland, A, Tarwater, B, Zandi, PP, Alda, M, Fisch, KM, Gage, FH & Kelsoe, JR 2023, 'Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis', Molecular Psychiatry. https://doi.org/10.1038/s41380-022-01909-9

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title = "Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis",

abstract = "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 (Phypergeometric= 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.",

author = "Vipavee Niemsiri and Rosenthal, {Sara Brin} and Nievergelt, {Caroline M.} and Maihofer, {Adam X.} and Marchetto, {Maria C.} and Renata Santos and Tatyana Shekhtman and Ney Alliey-Rodriguez and Amit Anand and Yokesh Balaraman and Berrettini, {Wade H.} and Holli Bertram and Burdick, {Katherine E.} and Calabrese, {Joseph R.} and Calkin, {Cynthia V.} and Carla Conroy and Coryell, {William H.} and Anna DeModena and Eyler, {Lisa T.} and Scott Feeder and Carrie Fisher and Nicole Frazier and Frye, {Mark A.} and Keming Gao and Julie Garnham and Gershon, {Elliot S.} and Goes, {Fernando S.} and Toyomi Goto and Harrington, {Gloria J.} and Petter Jakobsen and Masoud Kamali and Marisa Kelly and Leckband, {Susan G.} and Lohoff, {Falk W.} and McCarthy, {Michael J.} and McInnis, {Melvin G.} and David Craig and Millett, {Caitlin E.} and Francis Mondimore and Gunnar Morken and Nurnberger, {John I.} and Donovan, {Claire O{\textquoteright}} and {\O}edegaard, {Ketil J.} and Kelly Ryan and Martha Schinagle and Shilling, {Paul D.} and Claire Slaney and Stapp, {Emma K.} and Andrea Stautland and Bruce Tarwater and Zandi, {Peter P.} and Martin Alda and Fisch, {Kathleen M.} and Gage, {Fred H.} and Kelsoe, {John R.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

doi = "10.1038/s41380-022-01909-9",

language = "English (US)",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Focal adhesion is associated with lithium response in bipolar disorder

T2 - evidence from a network-based multi-omics analysis

AU - Niemsiri, Vipavee

AU - Rosenthal, Sara Brin

AU - Nievergelt, Caroline M.

AU - Maihofer, Adam X.

AU - Marchetto, Maria C.

AU - Santos, Renata

AU - Shekhtman, Tatyana

AU - Alliey-Rodriguez, Ney

AU - Anand, Amit

AU - Balaraman, Yokesh

AU - Berrettini, Wade H.

AU - Bertram, Holli

AU - Burdick, Katherine E.

AU - Calabrese, Joseph R.

AU - Calkin, Cynthia V.

AU - Conroy, Carla

AU - Coryell, William H.

AU - DeModena, Anna

AU - Eyler, Lisa T.

AU - Feeder, Scott

AU - Fisher, Carrie

AU - Frazier, Nicole

AU - Frye, Mark A.

AU - Gao, Keming

AU - Garnham, Julie

AU - Gershon, Elliot S.

AU - Goes, Fernando S.

AU - Goto, Toyomi

AU - Harrington, Gloria J.

AU - Jakobsen, Petter

AU - Kamali, Masoud

AU - Kelly, Marisa

AU - Leckband, Susan G.

AU - Lohoff, Falk W.

AU - McCarthy, Michael J.

AU - McInnis, Melvin G.

AU - Craig, David

AU - Millett, Caitlin E.

AU - Mondimore, Francis

AU - Morken, Gunnar

AU - Nurnberger, John I.

AU - Donovan, Claire O’

AU - Øedegaard, Ketil J.

AU - Ryan, Kelly

AU - Schinagle, Martha

AU - Shilling, Paul D.

AU - Slaney, Claire

AU - Stapp, Emma K.

AU - Stautland, Andrea

AU - Tarwater, Bruce

AU - Zandi, Peter P.

AU - Alda, Martin

AU - Fisch, Kathleen M.

AU - Gage, Fred H.

AU - Kelsoe, John R.

PY - 2023

Y1 - 2023

N2 - 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 (Phypergeometric= 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.

AB - 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 (Phypergeometric= 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.

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U2 - 10.1038/s41380-022-01909-9

DO - 10.1038/s41380-022-01909-9

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SN - 1359-4184

JO - Molecular Psychiatry

JF - Molecular Psychiatry

ER -

Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis

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