Genomewide Association Studies

History, Rationale, and Prospects for Psychiatric Disorders

Sven Cichon, Nick Craddock, Mark Daly, Stephen V. Faraone, Pablo V. Gejman, John Kelsoe, Thomas Lehner, Douglas F. Levinson, Audra Moran, Pamela Sklar, Patrick F. Sullivan, Richard Anney, Michael Gill, Aiden Corvin, Jan Buitelaar, Barbara Franke, Josephine Elia, Hakon Hakonarson, Lindsey Kent, James McGough & 103 others Susan Smalley, Roel Ophoff, Eric Mick, Susan Santangelo, Manuel Ferreira, Shaun Purcell, Douglas Ruderfer, Jordan Smoller, Roy Perlis, Ben Neale, Jennifer Stone, Laura Nisenbaum, Anita Thapar, Valentina Moskvina, Peter Holmans, Mike O'Donovan, Michael Owen, Richard Todd, Alexandre Todorov, John Rice, Bernie Devlin, Dan Arking, Aravinda Chakravarti, James B. Potash, Ann Pulver, Joseph D. Buxbaum, Edwin Cook, Leena Peltonen, Jaana Suvisaari, Joseph Piven, Danyu Lin, Patrick Sullivan, Guy Rouleau, Phillip Awadalla, Gerard Schellenberg, Steve Scherer, James Sutcliffe, Peter Szatmari, Veronica Vieland, Ole A. Andreassen, Arnoldo Frigessi, Douglas Blackwood, Walter Muir, Michael Boehnke, Margit Burmeister, Matthew Flickinger, Weihua Guan, Jun Li, Laura Scott, Rene Breuer, Marcella Rietschel, Thomas Schulze, Tiffany Greenwood, Nicholas Schork, Hugh Gurling, Pierandrea Muglia, Ruchi Upmanyu, Federica Tozzi, Markus Noethen, Thomas Wienker, Michael Steffens, John Nurnberger, Kenneth Kendler, Brien Riley, Edwin van den Oord, Dorret Boomsma, Eco de Geus, Witte Hoogendijk, Brenda Penninx, A. H M Willemsen, Danielle Posthuma, William Coryell, Steve Hamilton, Stafam Kloiber, Susanne Lucae, Stephan Ripke, William B. Lawson, Cathryn Lewis, Peter McGuffin, Nick Martin, Naomi Wray, Patrick McGrath, Myrna M. Weissman, James Offord, William A. Scheftner, Susan Slager, Ayman Fanous, Christina Hultman, Sari Kivikko, Claudine Laurent, Todd Lencz, Anil Malhotra, Bryan Mowry, Elizabeth Holliday, Alan Sanders, Sibylle Schwab, Dieter Wildenaver, David St. Clair, Frank Dudbridge, Eve Pickering, Danielle Posthuma, Jonathan Sebat, Jung Ying Tzeng

Research output: Contribution to journalArticle

298 Citations (Scopus)

Abstract

Objective: The authors conducted a review of the history and empirical basis of genomewide association studies (GWAS), the rationale for GWAS of psychiatric disorders, results to date, limitations, and plans for GWAS meta-analyses. Method: A literature review was carried out, power and other issues discussed, and planned studies assessed. Results: Most of the genomic DNA sequence differences between any two people are common (frequency >5%) single nucleotide polymorphisms (SNPs). Because of localized patterns of correlation (linkage disequilibrium), 500,000 to 1,000,000 of these SNPs can test the hypothesis that one or more common variants explain part of the genetic risk for a disease. GWAS technologies can also detect some of the copy number variants (deletions and duplications) in the genome. Systematic study of rare variants will require large-scale resequencing analyses. GWAS methods have detected a remarkable number of robust genetic associations for dozens of common diseases and traits, leading to new pathophysiological hypotheses, although only small proportions of genetic variance have been explained thus far and therapeutic applications will require substantial further effort. Study design issues, power, and limitations are discussed. For psychiatric disorders, there are initial significant findings for common SNPs and for rare copy number variants, and many other studies are in progress. Conclusions: GWAS of large samples have detected associations of common SNPs and of rare copy number variants with psychiatric disorders. More findings are likely, since larger GWAS samples detect larger numbers of common susceptibility variants, with smaller effects. The Psychiatric GWAS Consortium is conducting GWAS meta-analyses for schizophrenia, bipolar disorder, major depressive disorder, autism, and attention deficit hyperactivity disorder. Based on results for other diseases, larger samples will be required. The contribution of GWAS will depend on the true genetic architecture of each disorder.

Original languageEnglish
Pages (from-to)540-556
Number of pages17
JournalAmerican Journal of Psychiatry
Volume166
Issue number5
DOIs
StatePublished - May 2009

Fingerprint

Single Nucleotide Polymorphism
Psychiatry
History
Meta-Analysis
Linkage Disequilibrium
Major Depressive Disorder
Attention Deficit Disorder with Hyperactivity
Autistic Disorder
Bipolar Disorder
Schizophrenia
Genome
Technology
Power (Psychology)
Therapeutics

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Cichon, S., Craddock, N., Daly, M., Faraone, S. V., Gejman, P. V., Kelsoe, J., ... Tzeng, J. Y. (2009). Genomewide Association Studies: History, Rationale, and Prospects for Psychiatric Disorders. American Journal of Psychiatry, 166(5), 540-556. https://doi.org/10.1176/appi.ajp.2008.08091354

Genomewide Association Studies : History, Rationale, and Prospects for Psychiatric Disorders. / Cichon, Sven; Craddock, Nick; Daly, Mark; Faraone, Stephen V.; Gejman, Pablo V.; Kelsoe, John; Lehner, Thomas; Levinson, Douglas F.; Moran, Audra; Sklar, Pamela; Sullivan, Patrick F.; Anney, Richard; Gill, Michael; Corvin, Aiden; Buitelaar, Jan; Franke, Barbara; Elia, Josephine; Hakonarson, Hakon; Kent, Lindsey; McGough, James; Smalley, Susan; Ophoff, Roel; Mick, Eric; Santangelo, Susan; Ferreira, Manuel; Purcell, Shaun; Ruderfer, Douglas; Smoller, Jordan; Perlis, Roy; Neale, Ben; Stone, Jennifer; Nisenbaum, Laura; Thapar, Anita; Moskvina, Valentina; Holmans, Peter; O'Donovan, Mike; Owen, Michael; Todd, Richard; Todorov, Alexandre; Rice, John; Devlin, Bernie; Arking, Dan; Chakravarti, Aravinda; Potash, James B.; Pulver, Ann; Buxbaum, Joseph D.; Cook, Edwin; Peltonen, Leena; Suvisaari, Jaana; Piven, Joseph; Lin, Danyu; Sullivan, Patrick; Rouleau, Guy; Awadalla, Phillip; Schellenberg, Gerard; Scherer, Steve; Sutcliffe, James; Szatmari, Peter; Vieland, Veronica; Andreassen, Ole A.; Frigessi, Arnoldo; Blackwood, Douglas; Muir, Walter; Boehnke, Michael; Burmeister, Margit; Flickinger, Matthew; Guan, Weihua; Li, Jun; Scott, Laura; Breuer, Rene; Rietschel, Marcella; Schulze, Thomas; Greenwood, Tiffany; Schork, Nicholas; Gurling, Hugh; Muglia, Pierandrea; Upmanyu, Ruchi; Tozzi, Federica; Noethen, Markus; Wienker, Thomas; Steffens, Michael; Nurnberger, John; Kendler, Kenneth; Riley, Brien; van den Oord, Edwin; Boomsma, Dorret; de Geus, Eco; Hoogendijk, Witte; Penninx, Brenda; Willemsen, A. H M; Posthuma, Danielle; Coryell, William; Hamilton, Steve; Kloiber, Stafam; Lucae, Susanne; Ripke, Stephan; Lawson, William B.; Lewis, Cathryn; McGuffin, Peter; Martin, Nick; Wray, Naomi; McGrath, Patrick; Weissman, Myrna M.; Offord, James; Scheftner, William A.; Slager, Susan; Fanous, Ayman; Hultman, Christina; Kivikko, Sari; Laurent, Claudine; Lencz, Todd; Malhotra, Anil; Mowry, Bryan; Holliday, Elizabeth; Sanders, Alan; Schwab, Sibylle; Wildenaver, Dieter; St. Clair, David; Dudbridge, Frank; Pickering, Eve; Posthuma, Danielle; Sebat, Jonathan; Tzeng, Jung Ying.

In: American Journal of Psychiatry, Vol. 166, No. 5, 05.2009, p. 540-556.

Research output: Contribution to journalArticle

Cichon, S, Craddock, N, Daly, M, Faraone, SV, Gejman, PV, Kelsoe, J, Lehner, T, Levinson, DF, Moran, A, Sklar, P, Sullivan, PF, Anney, R, Gill, M, Corvin, A, Buitelaar, J, Franke, B, Elia, J, Hakonarson, H, Kent, L, McGough, J, Smalley, S, Ophoff, R, Mick, E, Santangelo, S, Ferreira, M, Purcell, S, Ruderfer, D, Smoller, J, Perlis, R, Neale, B, Stone, J, Nisenbaum, L, Thapar, A, Moskvina, V, Holmans, P, O'Donovan, M, Owen, M, Todd, R, Todorov, A, Rice, J, Devlin, B, Arking, D, Chakravarti, A, Potash, JB, Pulver, A, Buxbaum, JD, Cook, E, Peltonen, L, Suvisaari, J, Piven, J, Lin, D, Sullivan, P, Rouleau, G, Awadalla, P, Schellenberg, G, Scherer, S, Sutcliffe, J, Szatmari, P, Vieland, V, Andreassen, OA, Frigessi, A, Blackwood, D, Muir, W, Boehnke, M, Burmeister, M, Flickinger, M, Guan, W, Li, J, Scott, L, Breuer, R, Rietschel, M, Schulze, T, Greenwood, T, Schork, N, Gurling, H, Muglia, P, Upmanyu, R, Tozzi, F, Noethen, M, Wienker, T, Steffens, M, Nurnberger, J, Kendler, K, Riley, B, van den Oord, E, Boomsma, D, de Geus, E, Hoogendijk, W, Penninx, B, Willemsen, AHM, Posthuma, D, Coryell, W, Hamilton, S, Kloiber, S, Lucae, S, Ripke, S, Lawson, WB, Lewis, C, McGuffin, P, Martin, N, Wray, N, McGrath, P, Weissman, MM, Offord, J, Scheftner, WA, Slager, S, Fanous, A, Hultman, C, Kivikko, S, Laurent, C, Lencz, T, Malhotra, A, Mowry, B, Holliday, E, Sanders, A, Schwab, S, Wildenaver, D, St. Clair, D, Dudbridge, F, Pickering, E, Posthuma, D, Sebat, J & Tzeng, JY 2009, 'Genomewide Association Studies: History, Rationale, and Prospects for Psychiatric Disorders', American Journal of Psychiatry, vol. 166, no. 5, pp. 540-556. https://doi.org/10.1176/appi.ajp.2008.08091354
Cichon, Sven ; Craddock, Nick ; Daly, Mark ; Faraone, Stephen V. ; Gejman, Pablo V. ; Kelsoe, John ; Lehner, Thomas ; Levinson, Douglas F. ; Moran, Audra ; Sklar, Pamela ; Sullivan, Patrick F. ; Anney, Richard ; Gill, Michael ; Corvin, Aiden ; Buitelaar, Jan ; Franke, Barbara ; Elia, Josephine ; Hakonarson, Hakon ; Kent, Lindsey ; McGough, James ; Smalley, Susan ; Ophoff, Roel ; Mick, Eric ; Santangelo, Susan ; Ferreira, Manuel ; Purcell, Shaun ; Ruderfer, Douglas ; Smoller, Jordan ; Perlis, Roy ; Neale, Ben ; Stone, Jennifer ; Nisenbaum, Laura ; Thapar, Anita ; Moskvina, Valentina ; Holmans, Peter ; O'Donovan, Mike ; Owen, Michael ; Todd, Richard ; Todorov, Alexandre ; Rice, John ; Devlin, Bernie ; Arking, Dan ; Chakravarti, Aravinda ; Potash, James B. ; Pulver, Ann ; Buxbaum, Joseph D. ; Cook, Edwin ; Peltonen, Leena ; Suvisaari, Jaana ; Piven, Joseph ; Lin, Danyu ; Sullivan, Patrick ; Rouleau, Guy ; Awadalla, Phillip ; Schellenberg, Gerard ; Scherer, Steve ; Sutcliffe, James ; Szatmari, Peter ; Vieland, Veronica ; Andreassen, Ole A. ; Frigessi, Arnoldo ; Blackwood, Douglas ; Muir, Walter ; Boehnke, Michael ; Burmeister, Margit ; Flickinger, Matthew ; Guan, Weihua ; Li, Jun ; Scott, Laura ; Breuer, Rene ; Rietschel, Marcella ; Schulze, Thomas ; Greenwood, Tiffany ; Schork, Nicholas ; Gurling, Hugh ; Muglia, Pierandrea ; Upmanyu, Ruchi ; Tozzi, Federica ; Noethen, Markus ; Wienker, Thomas ; Steffens, Michael ; Nurnberger, John ; Kendler, Kenneth ; Riley, Brien ; van den Oord, Edwin ; Boomsma, Dorret ; de Geus, Eco ; Hoogendijk, Witte ; Penninx, Brenda ; Willemsen, A. H M ; Posthuma, Danielle ; Coryell, William ; Hamilton, Steve ; Kloiber, Stafam ; Lucae, Susanne ; Ripke, Stephan ; Lawson, William B. ; Lewis, Cathryn ; McGuffin, Peter ; Martin, Nick ; Wray, Naomi ; McGrath, Patrick ; Weissman, Myrna M. ; Offord, James ; Scheftner, William A. ; Slager, Susan ; Fanous, Ayman ; Hultman, Christina ; Kivikko, Sari ; Laurent, Claudine ; Lencz, Todd ; Malhotra, Anil ; Mowry, Bryan ; Holliday, Elizabeth ; Sanders, Alan ; Schwab, Sibylle ; Wildenaver, Dieter ; St. Clair, David ; Dudbridge, Frank ; Pickering, Eve ; Posthuma, Danielle ; Sebat, Jonathan ; Tzeng, Jung Ying. / Genomewide Association Studies : History, Rationale, and Prospects for Psychiatric Disorders. In: American Journal of Psychiatry. 2009 ; Vol. 166, No. 5. pp. 540-556.
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abstract = "Objective: The authors conducted a review of the history and empirical basis of genomewide association studies (GWAS), the rationale for GWAS of psychiatric disorders, results to date, limitations, and plans for GWAS meta-analyses. Method: A literature review was carried out, power and other issues discussed, and planned studies assessed. Results: Most of the genomic DNA sequence differences between any two people are common (frequency >5{\%}) single nucleotide polymorphisms (SNPs). Because of localized patterns of correlation (linkage disequilibrium), 500,000 to 1,000,000 of these SNPs can test the hypothesis that one or more common variants explain part of the genetic risk for a disease. GWAS technologies can also detect some of the copy number variants (deletions and duplications) in the genome. Systematic study of rare variants will require large-scale resequencing analyses. GWAS methods have detected a remarkable number of robust genetic associations for dozens of common diseases and traits, leading to new pathophysiological hypotheses, although only small proportions of genetic variance have been explained thus far and therapeutic applications will require substantial further effort. Study design issues, power, and limitations are discussed. For psychiatric disorders, there are initial significant findings for common SNPs and for rare copy number variants, and many other studies are in progress. Conclusions: GWAS of large samples have detected associations of common SNPs and of rare copy number variants with psychiatric disorders. More findings are likely, since larger GWAS samples detect larger numbers of common susceptibility variants, with smaller effects. The Psychiatric GWAS Consortium is conducting GWAS meta-analyses for schizophrenia, bipolar disorder, major depressive disorder, autism, and attention deficit hyperactivity disorder. Based on results for other diseases, larger samples will be required. The contribution of GWAS will depend on the true genetic architecture of each disorder.",
author = "Sven Cichon and Nick Craddock and Mark Daly and Faraone, {Stephen V.} and Gejman, {Pablo V.} and John Kelsoe and Thomas Lehner and Levinson, {Douglas F.} and Audra Moran and Pamela Sklar and Sullivan, {Patrick F.} and Richard Anney and Michael Gill and Aiden Corvin and Jan Buitelaar and Barbara Franke and Josephine Elia and Hakon Hakonarson and Lindsey Kent and James McGough and Susan Smalley and Roel Ophoff and Eric Mick and Susan Santangelo and Manuel Ferreira and Shaun Purcell and Douglas Ruderfer and Jordan Smoller and Roy Perlis and Ben Neale and Jennifer Stone and Laura Nisenbaum and Anita Thapar and Valentina Moskvina and Peter Holmans and Mike O'Donovan and Michael Owen and Richard Todd and Alexandre Todorov and John Rice and Bernie Devlin and Dan Arking and Aravinda Chakravarti and Potash, {James B.} and Ann Pulver and Buxbaum, {Joseph D.} and Edwin Cook and Leena Peltonen and Jaana Suvisaari and Joseph Piven and Danyu Lin and Patrick Sullivan and Guy Rouleau and Phillip Awadalla and Gerard Schellenberg and Steve Scherer and James Sutcliffe and Peter Szatmari and Veronica Vieland and Andreassen, {Ole A.} and Arnoldo Frigessi and Douglas Blackwood and Walter Muir and Michael Boehnke and Margit Burmeister and Matthew Flickinger and Weihua Guan and Jun Li and Laura Scott and Rene Breuer and Marcella Rietschel and Thomas Schulze and Tiffany Greenwood and Nicholas Schork and Hugh Gurling and Pierandrea Muglia and Ruchi Upmanyu and Federica Tozzi and Markus Noethen and Thomas Wienker and Michael Steffens and John Nurnberger and Kenneth Kendler and Brien Riley and {van den Oord}, Edwin and Dorret Boomsma and {de Geus}, Eco and Witte Hoogendijk and Brenda Penninx and Willemsen, {A. H M} and Danielle Posthuma and William Coryell and Steve Hamilton and Stafam Kloiber and Susanne Lucae and Stephan Ripke and Lawson, {William B.} and Cathryn Lewis and Peter McGuffin and Nick Martin and Naomi Wray and Patrick McGrath and Weissman, {Myrna M.} and James Offord and Scheftner, {William A.} and Susan Slager and Ayman Fanous and Christina Hultman and Sari Kivikko and Claudine Laurent and Todd Lencz and Anil Malhotra and Bryan Mowry and Elizabeth Holliday and Alan Sanders and Sibylle Schwab and Dieter Wildenaver and {St. Clair}, David and Frank Dudbridge and Eve Pickering and Danielle Posthuma and Jonathan Sebat and Tzeng, {Jung Ying}",
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T1 - Genomewide Association Studies

T2 - History, Rationale, and Prospects for Psychiatric Disorders

AU - Cichon, Sven

AU - Craddock, Nick

AU - Daly, Mark

AU - Faraone, Stephen V.

AU - Gejman, Pablo V.

AU - Kelsoe, John

AU - Lehner, Thomas

AU - Levinson, Douglas F.

AU - Moran, Audra

AU - Sklar, Pamela

AU - Sullivan, Patrick F.

AU - Anney, Richard

AU - Gill, Michael

AU - Corvin, Aiden

AU - Buitelaar, Jan

AU - Franke, Barbara

AU - Elia, Josephine

AU - Hakonarson, Hakon

AU - Kent, Lindsey

AU - McGough, James

AU - Smalley, Susan

AU - Ophoff, Roel

AU - Mick, Eric

AU - Santangelo, Susan

AU - Ferreira, Manuel

AU - Purcell, Shaun

AU - Ruderfer, Douglas

AU - Smoller, Jordan

AU - Perlis, Roy

AU - Neale, Ben

AU - Stone, Jennifer

AU - Nisenbaum, Laura

AU - Thapar, Anita

AU - Moskvina, Valentina

AU - Holmans, Peter

AU - O'Donovan, Mike

AU - Owen, Michael

AU - Todd, Richard

AU - Todorov, Alexandre

AU - Rice, John

AU - Devlin, Bernie

AU - Arking, Dan

AU - Chakravarti, Aravinda

AU - Potash, James B.

AU - Pulver, Ann

AU - Buxbaum, Joseph D.

AU - Cook, Edwin

AU - Peltonen, Leena

AU - Suvisaari, Jaana

AU - Piven, Joseph

AU - Lin, Danyu

AU - Sullivan, Patrick

AU - Rouleau, Guy

AU - Awadalla, Phillip

AU - Schellenberg, Gerard

AU - Scherer, Steve

AU - Sutcliffe, James

AU - Szatmari, Peter

AU - Vieland, Veronica

AU - Andreassen, Ole A.

AU - Frigessi, Arnoldo

AU - Blackwood, Douglas

AU - Muir, Walter

AU - Boehnke, Michael

AU - Burmeister, Margit

AU - Flickinger, Matthew

AU - Guan, Weihua

AU - Li, Jun

AU - Scott, Laura

AU - Breuer, Rene

AU - Rietschel, Marcella

AU - Schulze, Thomas

AU - Greenwood, Tiffany

AU - Schork, Nicholas

AU - Gurling, Hugh

AU - Muglia, Pierandrea

AU - Upmanyu, Ruchi

AU - Tozzi, Federica

AU - Noethen, Markus

AU - Wienker, Thomas

AU - Steffens, Michael

AU - Nurnberger, John

AU - Kendler, Kenneth

AU - Riley, Brien

AU - van den Oord, Edwin

AU - Boomsma, Dorret

AU - de Geus, Eco

AU - Hoogendijk, Witte

AU - Penninx, Brenda

AU - Willemsen, A. H M

AU - Posthuma, Danielle

AU - Coryell, William

AU - Hamilton, Steve

AU - Kloiber, Stafam

AU - Lucae, Susanne

AU - Ripke, Stephan

AU - Lawson, William B.

AU - Lewis, Cathryn

AU - McGuffin, Peter

AU - Martin, Nick

AU - Wray, Naomi

AU - McGrath, Patrick

AU - Weissman, Myrna M.

AU - Offord, James

AU - Scheftner, William A.

AU - Slager, Susan

AU - Fanous, Ayman

AU - Hultman, Christina

AU - Kivikko, Sari

AU - Laurent, Claudine

AU - Lencz, Todd

AU - Malhotra, Anil

AU - Mowry, Bryan

AU - Holliday, Elizabeth

AU - Sanders, Alan

AU - Schwab, Sibylle

AU - Wildenaver, Dieter

AU - St. Clair, David

AU - Dudbridge, Frank

AU - Pickering, Eve

AU - Posthuma, Danielle

AU - Sebat, Jonathan

AU - Tzeng, Jung Ying

PY - 2009/5

Y1 - 2009/5

N2 - Objective: The authors conducted a review of the history and empirical basis of genomewide association studies (GWAS), the rationale for GWAS of psychiatric disorders, results to date, limitations, and plans for GWAS meta-analyses. Method: A literature review was carried out, power and other issues discussed, and planned studies assessed. Results: Most of the genomic DNA sequence differences between any two people are common (frequency >5%) single nucleotide polymorphisms (SNPs). Because of localized patterns of correlation (linkage disequilibrium), 500,000 to 1,000,000 of these SNPs can test the hypothesis that one or more common variants explain part of the genetic risk for a disease. GWAS technologies can also detect some of the copy number variants (deletions and duplications) in the genome. Systematic study of rare variants will require large-scale resequencing analyses. GWAS methods have detected a remarkable number of robust genetic associations for dozens of common diseases and traits, leading to new pathophysiological hypotheses, although only small proportions of genetic variance have been explained thus far and therapeutic applications will require substantial further effort. Study design issues, power, and limitations are discussed. For psychiatric disorders, there are initial significant findings for common SNPs and for rare copy number variants, and many other studies are in progress. Conclusions: GWAS of large samples have detected associations of common SNPs and of rare copy number variants with psychiatric disorders. More findings are likely, since larger GWAS samples detect larger numbers of common susceptibility variants, with smaller effects. The Psychiatric GWAS Consortium is conducting GWAS meta-analyses for schizophrenia, bipolar disorder, major depressive disorder, autism, and attention deficit hyperactivity disorder. Based on results for other diseases, larger samples will be required. The contribution of GWAS will depend on the true genetic architecture of each disorder.

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JF - American Journal of Psychiatry

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