A genome-wide linkage and association scan reveals novel loci for autism

Lauren A. Weiss; Dan E. Arking; Mark J. Daly; Aravinda Chakravarti; Camille W. Brune; Kristen West; Ashley O'Connor; Gina Hilton; Rebecca L. Tomlinson; Andrew B. West; Edwin H. Cook; Todd Green; Shun Chiao Chang; Stacey Gabriel; Casey Gates; Ellen M. Hanson; Andrew Kirby; Joshua Korn; Finny Kuruvilla; Steven McCarroll; Eric M. Morrow; Benjamin Neale; Shaun Purcell; Roksana Sasanfar; Carrie Sougnez; Christine Stevens; David Altshuler; James Gusella; Susan L. Santangelo; Pamela Sklar; Rudolph Tanzi; Richard Anney; Anthony J. Bailey; Gillian Baird; Agatino Battaglia; Tom Berney; Catalina Betancur; Sven Bölte; Patrick F. Bolton; Jessica Brian; Susan E. Bryson; Joseph D. Buxbaum; Ines Cabrito; Guiqing Cai; Rita M. Cantor; Hilary Coon; Judith Conroy; Catarina Correia; Christina Corsello; Emily L. Crawford; Michael L. Cuccaro; Geraldine Dawson; Maretha De Jonge; Bernie Devlin; Eftichia Duketis; Sean Ennis; Annette Estes; Penny Farrar; Eric Fombonne; Christine M. Freitag; Louise Gallagher; Daniel H. Geschwind; John Gilbert; Michael Gill; Christopher Gillberg; Jeremy Goldberg; Andrew Green; Jonathan Green; Stephen J. Guter; Jonathan L. Haines; Joachim F. Hallmayer; Vanessa Hus; Sabine M. Klauck; Olena Korvatska; Janine A. Lamb; Magdalena Laskawiec; Marion Leboyer; Ann Le Couteur; Bennett L. Leventha; Xiao Qing Liu; Catherine Lord; Linda J. Lotspeich; Elena Maestrini; Tiago Magalhaes; William Mahoney; Carine Mantoulan; Helen McConachie; Christopher J. McDougle; William M. McMahon; Christian R. Marshall; Judith Miller; Nancy J. Minshew; Anthony P. Monaco; Jeff Munson; John I. Nurnberger; Guiomar Oliveira; Alistair Pagnamenta; Katerina Papanikolaou; Jeremy R. Parr; Andrew D. Paterson; Margaret A. Pericak-Vance; Andrew Pickles; Dalila Pinto; Joseph Piven; David J. Posey; Annemarie Poustka; Fritz Poustka; Regina Regan; Jennifer Reichert; Katy Renshaw; Wendy Roberts; Bernadette Roge; Michael L. Rutter; Jeff Salt; Gerard D. Schellenberg; Stephen W. Scherer; Val Sheffield; James S. Sutcliffe; Peter Szatmari; Katherine Tansey; Ann P. Thompson; John Tsiantis; Herman Van Engeland; Astrid M. Vicente; Veronica J. Vieland; Fred Volkmar; Simon Wallace; Thomas H. Wassink; Ellen M. Wijsman; Kirsty Wing; Kerstin Wittemeyer; Brian L. Yaspan; Lonnie Zwaigenbaum; Seung Yun Yoo; Robert Sean Hill; Nahit M. Mukaddes; Soher Balkhy; Generoso Gascon; Samira Al-Saad; Asif Hashmi; Janice Ware; Robert M. Joseph; Elaine LeClair; Jennifer N. Partlow; Brenda Barry; Christopher A. Walsh; David Pauls; Irma Moilanen; Hanna Ebeling; Marja Leena Mattila; Sanna Kuusikko; Katja Jussila; Jaakko Ignatius; Ala Tolouei; Majid Ghadami; Maryam Rostami; Azam Hosseinipour; Maryam Valujerdi; Kara Andresen; Brian Winkloski; Stephen Haddad; Lou Kunkel; Zak Kohane; Tram Tran; Sek Won Kong; Stephanie Brewster O'Neil; Rachel Hundley; Ingrid Holm; Heather Peters; Elizabeth Baroni; Aislyn Cangialose; Lindsay Jackson; Lisa Albers; Ronald Becker; Carolyn Bridgemohan; Sandra Friedman; Kerim Munir; Ramzi Nazir; Judith Palfrey; Alison Schonwald; Esau Simmons; Leonard A. Rappaport; Julie Gauthier; Laurent Mottron; Ridha Joober; Guy Rouleau; Karola Rehnstrom; Lennart Von Wendt; Leena Peltonen

doi:10.1038/nature08490

A genome-wide linkage and association scan reveals novel loci for autism

Lauren A. Weiss, Dan E. Arking, Mark J. Daly, Aravinda Chakravarti, Camille W. Brune, Kristen West, Ashley O'Connor, Gina Hilton, Rebecca L. Tomlinson, Andrew B. West, Edwin H. Cook, Todd Green, Shun Chiao Chang, Stacey Gabriel, Casey Gates, Ellen M. Hanson, Andrew Kirby, Joshua Korn, Finny Kuruvilla, Steven McCarrollEric M. Morrow, Benjamin Neale, Shaun Purcell, Roksana Sasanfar, Carrie Sougnez, Christine Stevens, David Altshuler, James Gusella, Susan L. Santangelo, Pamela Sklar, Rudolph Tanzi, Richard Anney, Anthony J. Bailey, Gillian Baird, Agatino Battaglia, Tom Berney, Catalina Betancur, Sven Bölte, Patrick F. Bolton, Jessica Brian, Susan E. Bryson, Joseph D. Buxbaum, Ines Cabrito, Guiqing Cai, Rita M. Cantor, Hilary Coon, Judith Conroy, Catarina Correia, Christina Corsello, Emily L. Crawford, Michael L. Cuccaro, Geraldine Dawson, Maretha De Jonge, Bernie Devlin, Eftichia Duketis, Sean Ennis, Annette Estes, Penny Farrar, Eric Fombonne, Christine M. Freitag, Louise Gallagher, Daniel H. Geschwind, John Gilbert, Michael Gill, Christopher Gillberg, Jeremy Goldberg, Andrew Green, Jonathan Green, Stephen J. Guter, Jonathan L. Haines, Joachim F. Hallmayer, Vanessa Hus, Sabine M. Klauck, Olena Korvatska, Janine A. Lamb, Magdalena Laskawiec, Marion Leboyer, Ann Le Couteur, Bennett L. Leventha, Xiao Qing Liu, Catherine Lord, Linda J. Lotspeich, Elena Maestrini, Tiago Magalhaes, William Mahoney, Carine Mantoulan, Helen McConachie, Christopher J. McDougle, William M. McMahon, Christian R. Marshall, Judith Miller, Nancy J. Minshew, Anthony P. Monaco, Jeff Munson, John I. Nurnberger, Guiomar Oliveira, Alistair Pagnamenta, Katerina Papanikolaou, Jeremy R. Parr, Andrew D. Paterson, Margaret A. Pericak-Vance, Andrew Pickles, Dalila Pinto, Joseph Piven, David J. Posey, Annemarie Poustka, Fritz Poustka, Regina Regan, Jennifer Reichert, Katy Renshaw, Wendy Roberts, Bernadette Roge, Michael L. Rutter, Jeff Salt, Gerard D. Schellenberg, Stephen W. Scherer, Val Sheffield, James S. Sutcliffe, Peter Szatmari, Katherine Tansey, Ann P. Thompson, John Tsiantis, Herman Van Engeland, Astrid M. Vicente, Veronica J. Vieland, Fred Volkmar, Simon Wallace, Thomas H. Wassink, Ellen M. Wijsman, Kirsty Wing, Kerstin Wittemeyer, Brian L. Yaspan, Lonnie Zwaigenbaum, Seung Yun Yoo, Robert Sean Hill, Nahit M. Mukaddes, Soher Balkhy, Generoso Gascon, Samira Al-Saad, Asif Hashmi, Janice Ware, Robert M. Joseph, Elaine LeClair, Jennifer N. Partlow, Brenda Barry, Christopher A. Walsh, David Pauls, Irma Moilanen, Hanna Ebeling, Marja Leena Mattila, Sanna Kuusikko, Katja Jussila, Jaakko Ignatius, Ala Tolouei, Majid Ghadami, Maryam Rostami, Azam Hosseinipour, Maryam Valujerdi, Kara Andresen, Brian Winkloski, Stephen Haddad, Lou Kunkel, Zak Kohane, Tram Tran, Sek Won Kong, Stephanie Brewster O'Neil, Rachel Hundley, Ingrid Holm, Heather Peters, Elizabeth Baroni, Aislyn Cangialose, Lindsay Jackson, Lisa Albers, Ronald Becker, Carolyn Bridgemohan, Sandra Friedman, Kerim Munir, Ramzi Nazir, Judith Palfrey, Alison Schonwald, Esau Simmons, Leonard A. Rappaport, Julie Gauthier, Laurent Mottron, Ridha Joober, Guy Rouleau, Karola Rehnstrom, Lennart Von Wendt, Leena Peltonen

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

514 Scopus citations

Abstract

Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10-7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.

Original language	English (US)
Pages (from-to)	802-808
Number of pages	7
Journal	Nature
Volume	461
Issue number	7265
DOIs	https://doi.org/10.1038/nature08490
State	Published - Oct 8 2009
Externally published	Yes

ASJC Scopus subject areas

General

Access to Document

10.1038/nature08490

Cite this

Weiss, L. A., Arking, D. E., Daly, M. J., Chakravarti, A., Brune, C. W., West, K., O'Connor, A., Hilton, G., Tomlinson, R. L., West, A. B., Cook, E. H., Green, T., Chang, S. C., Gabriel, S., Gates, C., Hanson, E. M., Kirby, A., Korn, J., Kuruvilla, F., ... Peltonen, L. (2009). A genome-wide linkage and association scan reveals novel loci for autism. Nature, 461(7265), 802-808. https://doi.org/10.1038/nature08490

Weiss, LA, Arking, DE, Daly, MJ, Chakravarti, A, Brune, CW, West, K, O'Connor, A, Hilton, G, Tomlinson, RL, West, AB, Cook, EH, Green, T, Chang, SC, Gabriel, S, Gates, C, Hanson, EM, Kirby, A, Korn, J, Kuruvilla, F, McCarroll, S, Morrow, EM, Neale, B, Purcell, S, Sasanfar, R, Sougnez, C, Stevens, C, Altshuler, D, Gusella, J, Santangelo, SL, Sklar, P, Tanzi, R, Anney, R, Bailey, AJ, Baird, G, Battaglia, A, Berney, T, Betancur, C, Bölte, S, Bolton, PF, Brian, J, Bryson, SE, Buxbaum, JD, Cabrito, I, Cai, G, Cantor, RM, Coon, H, Conroy, J, Correia, C, Corsello, C, Crawford, EL, Cuccaro, ML, Dawson, G, De Jonge, M, Devlin, B, Duketis, E, Ennis, S, Estes, A, Farrar, P, Fombonne, E, Freitag, CM, Gallagher, L, Geschwind, DH, Gilbert, J, Gill, M, Gillberg, C, Goldberg, J, Green, A, Green, J, Guter, SJ, Haines, JL, Hallmayer, JF, Hus, V, Klauck, SM, Korvatska, O, Lamb, JA, Laskawiec, M, Leboyer, M, Le Couteur, A, Leventha, BL, Liu, XQ, Lord, C, Lotspeich, LJ, Maestrini, E, Magalhaes, T, Mahoney, W, Mantoulan, C, McConachie, H, McDougle, CJ, McMahon, WM, Marshall, CR, Miller, J, Minshew, NJ, Monaco, AP, Munson, J, Nurnberger, JI, Oliveira, G, Pagnamenta, A, Papanikolaou, K, Parr, JR, Paterson, AD, Pericak-Vance, MA, Pickles, A, Pinto, D, Piven, J, Posey, DJ, Poustka, A, Poustka, F, Regan, R, Reichert, J, Renshaw, K, Roberts, W, Roge, B, Rutter, ML, Salt, J, Schellenberg, GD, Scherer, SW, Sheffield, V, Sutcliffe, JS, Szatmari, P, Tansey, K, Thompson, AP, Tsiantis, J, Van Engeland, H, Vicente, AM, Vieland, VJ, Volkmar, F, Wallace, S, Wassink, TH, Wijsman, EM, Wing, K, Wittemeyer, K, Yaspan, BL, Zwaigenbaum, L, Yoo, SY, Hill, RS, Mukaddes, NM, Balkhy, S, Gascon, G, Al-Saad, S, Hashmi, A, Ware, J, Joseph, RM, LeClair, E, Partlow, JN, Barry, B, Walsh, CA, Pauls, D, Moilanen, I, Ebeling, H, Mattila, ML, Kuusikko, S, Jussila, K, Ignatius, J, Tolouei, A, Ghadami, M, Rostami, M, Hosseinipour, A, Valujerdi, M, Andresen, K, Winkloski, B, Haddad, S, Kunkel, L, Kohane, Z, Tran, T, Won Kong, S, O'Neil, SB, Hundley, R, Holm, I, Peters, H, Baroni, E, Cangialose, A, Jackson, L, Albers, L, Becker, R, Bridgemohan, C, Friedman, S, Munir, K, Nazir, R, Palfrey, J, Schonwald, A, Simmons, E, Rappaport, LA, Gauthier, J, Mottron, L, Joober, R, Rouleau, G, Rehnstrom, K, Von Wendt, L & Peltonen, L 2009, 'A genome-wide linkage and association scan reveals novel loci for autism', Nature, vol. 461, no. 7265, pp. 802-808. https://doi.org/10.1038/nature08490

@article{61cd801c916c40e1a30e70aaf6b24df7,

title = "A genome-wide linkage and association scan reveals novel loci for autism",

abstract = "Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10-7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.",

author = "Weiss, {Lauren A.} and Arking, {Dan E.} and Daly, {Mark J.} and Aravinda Chakravarti and Brune, {Camille W.} and Kristen West and Ashley O'Connor and Gina Hilton and Tomlinson, {Rebecca L.} and West, {Andrew B.} and Cook, {Edwin H.} and Todd Green and Chang, {Shun Chiao} and Stacey Gabriel and Casey Gates and Hanson, {Ellen M.} and Andrew Kirby and Joshua Korn and Finny Kuruvilla and Steven McCarroll and Morrow, {Eric M.} and Benjamin Neale and Shaun Purcell and Roksana Sasanfar and Carrie Sougnez and Christine Stevens and David Altshuler and James Gusella and Santangelo, {Susan L.} and Pamela Sklar and Rudolph Tanzi and Richard Anney and Bailey, {Anthony J.} and Gillian Baird and Agatino Battaglia and Tom Berney and Catalina Betancur and Sven B{\"o}lte and Bolton, {Patrick F.} and Jessica Brian and Bryson, {Susan E.} and Buxbaum, {Joseph D.} and Ines Cabrito and Guiqing Cai and Cantor, {Rita M.} and Hilary Coon and Judith Conroy and Catarina Correia and Christina Corsello and Crawford, {Emily L.} and Cuccaro, {Michael L.} and Geraldine Dawson and {De Jonge}, Maretha and Bernie Devlin and Eftichia Duketis and Sean Ennis and Annette Estes and Penny Farrar and Eric Fombonne and Freitag, {Christine M.} and Louise Gallagher and Geschwind, {Daniel H.} and John Gilbert and Michael Gill and Christopher Gillberg and Jeremy Goldberg and Andrew Green and Jonathan Green and Guter, {Stephen J.} and Haines, {Jonathan L.} and Hallmayer, {Joachim F.} and Vanessa Hus and Klauck, {Sabine M.} and Olena Korvatska and Lamb, {Janine A.} and Magdalena Laskawiec and Marion Leboyer and {Le Couteur}, Ann and Leventha, {Bennett L.} and Liu, {Xiao Qing} and Catherine Lord and Lotspeich, {Linda J.} and Elena Maestrini and Tiago Magalhaes and William Mahoney and Carine Mantoulan and Helen McConachie and McDougle, {Christopher J.} and McMahon, {William M.} and Marshall, {Christian R.} and Judith Miller and Minshew, {Nancy J.} and Monaco, {Anthony P.} and Jeff Munson and Nurnberger, {John I.} and Guiomar Oliveira and Alistair Pagnamenta and Katerina Papanikolaou and Parr, {Jeremy R.} and Paterson, {Andrew D.} and Pericak-Vance, {Margaret A.} and Andrew Pickles and Dalila Pinto and Joseph Piven and Posey, {David J.} and Annemarie Poustka and Fritz Poustka and Regina Regan and Jennifer Reichert and Katy Renshaw and Wendy Roberts and Bernadette Roge and Rutter, {Michael L.} and Jeff Salt and Schellenberg, {Gerard D.} and Scherer, {Stephen W.} and Val Sheffield and Sutcliffe, {James S.} and Peter Szatmari and Katherine Tansey and Thompson, {Ann P.} and John Tsiantis and {Van Engeland}, Herman and Vicente, {Astrid M.} and Vieland, {Veronica J.} and Fred Volkmar and Simon Wallace and Wassink, {Thomas H.} and Wijsman, {Ellen M.} and Kirsty Wing and Kerstin Wittemeyer and Yaspan, {Brian L.} and Lonnie Zwaigenbaum and Yoo, {Seung Yun} and Hill, {Robert Sean} and Mukaddes, {Nahit M.} and Soher Balkhy and Generoso Gascon and Samira Al-Saad and Asif Hashmi and Janice Ware and Joseph, {Robert M.} and Elaine LeClair and Partlow, {Jennifer N.} and Brenda Barry and Walsh, {Christopher A.} and David Pauls and Irma Moilanen and Hanna Ebeling and Mattila, {Marja Leena} and Sanna Kuusikko and Katja Jussila and Jaakko Ignatius and Ala Tolouei and Majid Ghadami and Maryam Rostami and Azam Hosseinipour and Maryam Valujerdi and Kara Andresen and Brian Winkloski and Stephen Haddad and Lou Kunkel and Zak Kohane and Tram Tran and {Won Kong}, Sek and O'Neil, {Stephanie Brewster} and Rachel Hundley and Ingrid Holm and Heather Peters and Elizabeth Baroni and Aislyn Cangialose and Lindsay Jackson and Lisa Albers and Ronald Becker and Carolyn Bridgemohan and Sandra Friedman and Kerim Munir and Ramzi Nazir and Judith Palfrey and Alison Schonwald and Esau Simmons and Rappaport, {Leonard A.} and Julie Gauthier and Laurent Mottron and Ridha Joober and Guy Rouleau and Karola Rehnstrom and {Von Wendt}, Lennart and Leena Peltonen",

note = "Funding Information: Acknowledgements We thank all of the families who have participated in and contributed to the public resources that we have used in these studies. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources. The Gene Discovery Project of Johns Hopkins was funded by grants from the National Institutes of Mental Health (MH60007, MH081754) and the Simons Foundation. This study was funded in part through a grant from the Autism Consortium of Boston. Support for the Extreme Discordant Sib-Pair (EDSP) family sample was provided by the NLM Family foundation. Support for the Massachusetts General Hospital (MGH)–Finnish collaborative sample was provided by NARSAD. Support for the Homozygosity Mapping Collaborative for Autism (HMCA) came from NIMH (1R01 MH083565), the Nancy Lurie Marks (NLM) Family Foundation and the Simons Foundation. Eric M. Morrow is supported by the NIMH (1K23MH080954). Support for the Iranian family sample was provided by the Special Education Organization of Iran, under the Iranian Ministry of Education. Lauren A. Weiss was supported by a Ruth L. Kirschstein National Research Service Award and is currently supported by the International Mental Health Research Organization. The collection of data and biomaterials that participated in the National Institute of Mental Health (NIMH) Autism Genetics Initiative has been supported by National Institute of Health grants MH52708, MH39437, MH00219 and MH00980; National Health Medical Research Council grant 0034328; and by grants from the Scottish Rite, the Spunk Fund, Inc., the Rebecca and Solomon Baker Fund, the APEX Foundation, the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD), and the endowment fund of the Nancy Pritzker Laboratory (Stanford); and by gifts from the Autism Society of America, the Janet M. Grace Pervasive Developmental Disorders Fund, and families and friends of individuals with autism. The NIMH collection Principal Investigators and Co-Investigators were: Neil Risch, Richard M. Myers, Donna Spiker, Linda J. Lotspeich, Joachim F. Hallmayer, Helena C. Kraemer, Roland D. Ciaranello, Luigi Luca Cavalli-Sforza (Stanford University, Stanford); William M. McMahon and P. Brent Petersen (University of Utah, Salt Lake City). The Stanford team is indebted to the parent groups and clinician colleagues who referred families and extends their gratitude to the families with individuals with autism who were partners in this research. The collection data and biomaterials also come from the Autism Genetic Resource Exchange (AGRE) collection. This program has been supported by a National Institute of Health grant MH64547 and the Cure Autism Now Foundation. The AGRE collection Principal Investigator is Daniel H. Geschwind (UCLA). The Co-Principal Investigators include Stanley F. Nelson and Rita M. Cantor (UCLA), Christa Lese Martin (Univ. Chicago), T. Conrad Gilliam (Columbia). Co-Investigators include Maricela Alarcon (UCLA), Kenneth Lange (UCLA), Sarah J. Spence (UCLA), David H. Ledbetter (Emory) and Hank Juo (Columbia). Scientific oversight of the AGRE program is provided by a steering committee (Chair: Daniel H. Geschwind; Members: W. Ted Brown, Maja Bucan, Joseph D. Buxbaum, T. Conrad Gilliam, David Greenberg, David H. Ledbetter, Bruce Miller, Stanley F. Nelson, Jonathan Pevsner, Carol Sprouse, Gerard D. Schellenberg and Rudolph Tanzi). The Autism Genome Project (AGP) work was supported by the following grants: (1) The Hilibrand Foundation (Principal Investigator Joachim F. Hallmayer); (2) Autism Speaks (for the AGP); (3) grants from the National Institutes of Health (NIH) MH61009 (James S. Sutcliffe), MH55135 (Susan E. Folstein), MH55284 (Joseph Piven), HD055782 (Ellen M. Wijsman), NS042165 (Joachim F. Hallmayer); (4) Fundac¸{\~a}o para a Ci{\^e}ncia e Tecnologia (POCTI/39636/ESP/ 2001) Fundac¸{\~a}o Calouste Gulbenkian (Astrid Vincente); (5) INSERM, Fondation de France, Fondation Orange, Fondation pour la Recherche M{\'e}dicale (Catalina Betancur, Marion Leboyer), and the Swedish Science Council (Christopher Gillberg); (6) The Seaver Foundation (Joseph D. Buxbaum); (7) The Children{\textquoteright}s Medical & Research Foundation (CMRF), Our Lady{\textquoteright}s Children{\textquoteright}s Hospital, Crumlin, Ireland (Sean Ennis); (8) The Medical Research Council (MRC) (Anthony P. Monaco, Anthony J. Bailey). Fresh-frozen brain tissue samples were obtained through the Autism Tissue Program and the Harvard Brain Bank.",

year = "2009",

month = oct,

day = "8",

doi = "10.1038/nature08490",

language = "English (US)",

volume = "461",

pages = "802--808",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7265",

}

TY - JOUR

T1 - A genome-wide linkage and association scan reveals novel loci for autism

AU - Weiss, Lauren A.

AU - Arking, Dan E.

AU - Daly, Mark J.

AU - Chakravarti, Aravinda

AU - Brune, Camille W.

AU - West, Kristen

AU - O'Connor, Ashley

AU - Hilton, Gina

AU - Tomlinson, Rebecca L.

AU - West, Andrew B.

AU - Cook, Edwin H.

AU - Green, Todd

AU - Chang, Shun Chiao

AU - Gabriel, Stacey

AU - Gates, Casey

AU - Hanson, Ellen M.

AU - Kirby, Andrew

AU - Korn, Joshua

AU - Kuruvilla, Finny

AU - McCarroll, Steven

AU - Morrow, Eric M.

AU - Neale, Benjamin

AU - Purcell, Shaun

AU - Sasanfar, Roksana

AU - Sougnez, Carrie

AU - Stevens, Christine

AU - Altshuler, David

AU - Gusella, James

AU - Santangelo, Susan L.

AU - Sklar, Pamela

AU - Tanzi, Rudolph

AU - Anney, Richard

AU - Bailey, Anthony J.

AU - Baird, Gillian

AU - Battaglia, Agatino

AU - Berney, Tom

AU - Betancur, Catalina

AU - Bölte, Sven

AU - Bolton, Patrick F.

AU - Brian, Jessica

AU - Bryson, Susan E.

AU - Buxbaum, Joseph D.

AU - Cabrito, Ines

AU - Cai, Guiqing

AU - Cantor, Rita M.

AU - Coon, Hilary

AU - Conroy, Judith

AU - Correia, Catarina

AU - Corsello, Christina

AU - Crawford, Emily L.

AU - Cuccaro, Michael L.

AU - Dawson, Geraldine

AU - De Jonge, Maretha

AU - Devlin, Bernie

AU - Duketis, Eftichia

AU - Ennis, Sean

AU - Estes, Annette

AU - Farrar, Penny

AU - Fombonne, Eric

AU - Freitag, Christine M.

AU - Gallagher, Louise

AU - Geschwind, Daniel H.

AU - Gilbert, John

AU - Gill, Michael

AU - Gillberg, Christopher

AU - Goldberg, Jeremy

AU - Green, Andrew

AU - Green, Jonathan

AU - Guter, Stephen J.

AU - Haines, Jonathan L.

AU - Hallmayer, Joachim F.

AU - Hus, Vanessa

AU - Klauck, Sabine M.

AU - Korvatska, Olena

AU - Lamb, Janine A.

AU - Laskawiec, Magdalena

AU - Leboyer, Marion

AU - Le Couteur, Ann

AU - Leventha, Bennett L.

AU - Liu, Xiao Qing

AU - Lord, Catherine

AU - Lotspeich, Linda J.

AU - Maestrini, Elena

AU - Magalhaes, Tiago

AU - Mahoney, William

AU - Mantoulan, Carine

AU - McConachie, Helen

AU - McDougle, Christopher J.

AU - McMahon, William M.

AU - Marshall, Christian R.

AU - Miller, Judith

AU - Minshew, Nancy J.

AU - Monaco, Anthony P.

AU - Munson, Jeff

AU - Nurnberger, John I.

AU - Oliveira, Guiomar

AU - Pagnamenta, Alistair

AU - Papanikolaou, Katerina

AU - Parr, Jeremy R.

AU - Paterson, Andrew D.

AU - Pericak-Vance, Margaret A.

AU - Pickles, Andrew

AU - Pinto, Dalila

AU - Piven, Joseph

AU - Posey, David J.

AU - Poustka, Annemarie

AU - Poustka, Fritz

AU - Regan, Regina

AU - Reichert, Jennifer

AU - Renshaw, Katy

AU - Roberts, Wendy

AU - Roge, Bernadette

AU - Rutter, Michael L.

AU - Salt, Jeff

AU - Schellenberg, Gerard D.

AU - Scherer, Stephen W.

AU - Sheffield, Val

AU - Sutcliffe, James S.

AU - Szatmari, Peter

AU - Tansey, Katherine

AU - Thompson, Ann P.

AU - Tsiantis, John

AU - Van Engeland, Herman

AU - Vicente, Astrid M.

AU - Vieland, Veronica J.

AU - Volkmar, Fred

AU - Wallace, Simon

AU - Wassink, Thomas H.

AU - Wijsman, Ellen M.

AU - Wing, Kirsty

AU - Wittemeyer, Kerstin

AU - Yaspan, Brian L.

AU - Zwaigenbaum, Lonnie

AU - Yoo, Seung Yun

AU - Hill, Robert Sean

AU - Mukaddes, Nahit M.

AU - Balkhy, Soher

AU - Gascon, Generoso

AU - Al-Saad, Samira

AU - Hashmi, Asif

AU - Ware, Janice

AU - Joseph, Robert M.

AU - LeClair, Elaine

AU - Partlow, Jennifer N.

AU - Barry, Brenda

AU - Walsh, Christopher A.

AU - Pauls, David

AU - Moilanen, Irma

AU - Ebeling, Hanna

AU - Mattila, Marja Leena

AU - Kuusikko, Sanna

AU - Jussila, Katja

AU - Ignatius, Jaakko

AU - Tolouei, Ala

AU - Ghadami, Majid

AU - Rostami, Maryam

AU - Hosseinipour, Azam

AU - Valujerdi, Maryam

AU - Andresen, Kara

AU - Winkloski, Brian

AU - Haddad, Stephen

AU - Kunkel, Lou

AU - Kohane, Zak

AU - Tran, Tram

AU - Won Kong, Sek

AU - O'Neil, Stephanie Brewster

AU - Hundley, Rachel

AU - Holm, Ingrid

AU - Peters, Heather

AU - Baroni, Elizabeth

AU - Cangialose, Aislyn

AU - Jackson, Lindsay

AU - Albers, Lisa

AU - Becker, Ronald

AU - Bridgemohan, Carolyn

AU - Friedman, Sandra

AU - Munir, Kerim

AU - Nazir, Ramzi

AU - Palfrey, Judith

AU - Schonwald, Alison

AU - Simmons, Esau

AU - Rappaport, Leonard A.

AU - Gauthier, Julie

AU - Mottron, Laurent

AU - Joober, Ridha

AU - Rouleau, Guy

AU - Rehnstrom, Karola

AU - Von Wendt, Lennart

AU - Peltonen, Leena

N1 - Funding Information: Acknowledgements We thank all of the families who have participated in and contributed to the public resources that we have used in these studies. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources. The Gene Discovery Project of Johns Hopkins was funded by grants from the National Institutes of Mental Health (MH60007, MH081754) and the Simons Foundation. This study was funded in part through a grant from the Autism Consortium of Boston. Support for the Extreme Discordant Sib-Pair (EDSP) family sample was provided by the NLM Family foundation. Support for the Massachusetts General Hospital (MGH)–Finnish collaborative sample was provided by NARSAD. Support for the Homozygosity Mapping Collaborative for Autism (HMCA) came from NIMH (1R01 MH083565), the Nancy Lurie Marks (NLM) Family Foundation and the Simons Foundation. Eric M. Morrow is supported by the NIMH (1K23MH080954). Support for the Iranian family sample was provided by the Special Education Organization of Iran, under the Iranian Ministry of Education. Lauren A. Weiss was supported by a Ruth L. Kirschstein National Research Service Award and is currently supported by the International Mental Health Research Organization. The collection of data and biomaterials that participated in the National Institute of Mental Health (NIMH) Autism Genetics Initiative has been supported by National Institute of Health grants MH52708, MH39437, MH00219 and MH00980; National Health Medical Research Council grant 0034328; and by grants from the Scottish Rite, the Spunk Fund, Inc., the Rebecca and Solomon Baker Fund, the APEX Foundation, the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD), and the endowment fund of the Nancy Pritzker Laboratory (Stanford); and by gifts from the Autism Society of America, the Janet M. Grace Pervasive Developmental Disorders Fund, and families and friends of individuals with autism. The NIMH collection Principal Investigators and Co-Investigators were: Neil Risch, Richard M. Myers, Donna Spiker, Linda J. Lotspeich, Joachim F. Hallmayer, Helena C. Kraemer, Roland D. Ciaranello, Luigi Luca Cavalli-Sforza (Stanford University, Stanford); William M. McMahon and P. Brent Petersen (University of Utah, Salt Lake City). The Stanford team is indebted to the parent groups and clinician colleagues who referred families and extends their gratitude to the families with individuals with autism who were partners in this research. The collection data and biomaterials also come from the Autism Genetic Resource Exchange (AGRE) collection. This program has been supported by a National Institute of Health grant MH64547 and the Cure Autism Now Foundation. The AGRE collection Principal Investigator is Daniel H. Geschwind (UCLA). The Co-Principal Investigators include Stanley F. Nelson and Rita M. Cantor (UCLA), Christa Lese Martin (Univ. Chicago), T. Conrad Gilliam (Columbia). Co-Investigators include Maricela Alarcon (UCLA), Kenneth Lange (UCLA), Sarah J. Spence (UCLA), David H. Ledbetter (Emory) and Hank Juo (Columbia). Scientific oversight of the AGRE program is provided by a steering committee (Chair: Daniel H. Geschwind; Members: W. Ted Brown, Maja Bucan, Joseph D. Buxbaum, T. Conrad Gilliam, David Greenberg, David H. Ledbetter, Bruce Miller, Stanley F. Nelson, Jonathan Pevsner, Carol Sprouse, Gerard D. Schellenberg and Rudolph Tanzi). The Autism Genome Project (AGP) work was supported by the following grants: (1) The Hilibrand Foundation (Principal Investigator Joachim F. Hallmayer); (2) Autism Speaks (for the AGP); (3) grants from the National Institutes of Health (NIH) MH61009 (James S. Sutcliffe), MH55135 (Susan E. Folstein), MH55284 (Joseph Piven), HD055782 (Ellen M. Wijsman), NS042165 (Joachim F. Hallmayer); (4) Fundac¸ão para a Ciência e Tecnologia (POCTI/39636/ESP/ 2001) Fundac¸ão Calouste Gulbenkian (Astrid Vincente); (5) INSERM, Fondation de France, Fondation Orange, Fondation pour la Recherche Médicale (Catalina Betancur, Marion Leboyer), and the Swedish Science Council (Christopher Gillberg); (6) The Seaver Foundation (Joseph D. Buxbaum); (7) The Children’s Medical & Research Foundation (CMRF), Our Lady’s Children’s Hospital, Crumlin, Ireland (Sean Ennis); (8) The Medical Research Council (MRC) (Anthony P. Monaco, Anthony J. Bailey). Fresh-frozen brain tissue samples were obtained through the Autism Tissue Program and the Harvard Brain Bank.

PY - 2009/10/8

Y1 - 2009/10/8

N2 - Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10-7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.

AB - Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10-7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.

UR - http://www.scopus.com/inward/record.url?scp=70349956425&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70349956425&partnerID=8YFLogxK

U2 - 10.1038/nature08490

DO - 10.1038/nature08490

M3 - Article

C2 - 19812673

AN - SCOPUS:70349956425

SN - 0028-0836

VL - 461

SP - 802

EP - 808

JO - Nature

JF - Nature

IS - 7265

ER -

A genome-wide linkage and association scan reveals novel loci for autism

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