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 |
|---|---|
| Pages (from-to) | 802-808 |
| Number of pages | 7 |
| Journal | Nature |
| Volume | 461 |
| Issue number | 7265 |
| DOIs | |
| Publication status | Published - Oct 8 2009 |
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A genome-wide linkage and association scan reveals novel loci for autism. / Weiss, Lauren A.; Arking, Dan E.; Daly, Mark J.; Chakravarti, Aravinda; Brune, Camille W.; West, Kristen; O'Connor, Ashley; Hilton, Gina; Tomlinson, Rebecca L.; West, Andrew B.; Cook, Edwin H.; Green, Todd; Chang, Shun Chiao; Gabriel, Stacey; Gates, Casey; Hanson, Ellen M.; Kirby, Andrew; Korn, Joshua; Kuruvilla, Finny; McCarroll, Steven; Morrow, Eric M.; Neale, Benjamin; Purcell, Shaun; Sasanfar, Roksana; Sougnez, Carrie; Stevens, Christine; Altshuler, David; Gusella, James; Santangelo, Susan L.; Sklar, Pamela; Tanzi, Rudolph; Anney, Richard; Bailey, Anthony J.; Baird, Gillian; Battaglia, Agatino; Berney, Tom; Betancur, Catalina; Bölte, Sven; Bolton, Patrick F.; Brian, Jessica; Bryson, Susan E.; Buxbaum, Joseph D.; Cabrito, Ines; Cai, Guiqing; Cantor, Rita M.; Coon, Hilary; Conroy, Judith; Correia, Catarina; Corsello, Christina; Crawford, Emily L.; Cuccaro, Michael L.; Dawson, Geraldine; De Jonge, Maretha; Devlin, Bernie; Duketis, Eftichia; Ennis, Sean; Estes, Annette; Farrar, Penny; Fombonne, Eric; Freitag, Christine M.; Gallagher, Louise; Geschwind, Daniel H.; Gilbert, John; Gill, Michael; Gillberg, Christopher; Goldberg, Jeremy; Green, Andrew; Green, Jonathan; Guter, Stephen J.; Haines, Jonathan L.; Hallmayer, Joachim F.; Hus, Vanessa; Klauck, Sabine M.; Korvatska, Olena; Lamb, Janine A.; Laskawiec, Magdalena; Leboyer, Marion; Le Couteur, Ann; Leventha, Bennett L.; Liu, Xiao Qing; Lord, Catherine; Lotspeich, Linda J.; Maestrini, Elena; Magalhaes, Tiago; Mahoney, William; Mantoulan, Carine; McConachie, Helen; McDougle, Christopher J.; McMahon, William M.; Marshall, Christian R.; Miller, Judith; Minshew, Nancy J.; Monaco, Anthony P.; Munson, Jeff; Nurnberger, John I.; Oliveira, Guiomar; Pagnamenta, Alistair; Papanikolaou, Katerina; Parr, Jeremy R.; Paterson, Andrew D.; Pericak-Vance, Margaret A.; Pickles, Andrew; Pinto, Dalila; Piven, Joseph; Posey, David J.; Poustka, Annemarie; Poustka, Fritz; Regan, Regina; Reichert, Jennifer; Renshaw, Katy; Roberts, Wendy; Roge, Bernadette; Rutter, Michael L.; Salt, Jeff; Schellenberg, Gerard D.; Scherer, Stephen W.; Sheffield, Val; Sutcliffe, James S.; Szatmari, Peter; Tansey, Katherine; Thompson, Ann P.; Tsiantis, John; Van Engeland, Herman; Vicente, Astrid M.; Vieland, Veronica J.; Volkmar, Fred; Wallace, Simon; Wassink, Thomas H.; Wijsman, Ellen M.; Wing, Kirsty; Wittemeyer, Kerstin; Yaspan, Brian L.; Zwaigenbaum, Lonnie; Yoo, Seung Yun; Hill, Robert Sean; Mukaddes, Nahit M.; Balkhy, Soher; Gascon, Generoso; Al-Saad, Samira; Hashmi, Asif; Ware, Janice; Joseph, Robert M.; LeClair, Elaine; Partlow, Jennifer N.; Barry, Brenda; Walsh, Christopher A.; Pauls, David; Moilanen, Irma; Ebeling, Hanna; Mattila, Marja Leena; Kuusikko, Sanna; Jussila, Katja; Ignatius, Jaakko; Tolouei, Ala; Ghadami, Majid; Rostami, Maryam; Hosseinipour, Azam; Valujerdi, Maryam; Andresen, Kara; Winkloski, Brian; Haddad, Stephen; Kunkel, Lou; Kohane, Zak; Tran, Tram; Won Kong, Sek; O'Neil, Stephanie Brewster; Hundley, Rachel; Holm, Ingrid; Peters, Heather; Baroni, Elizabeth; Cangialose, Aislyn; Jackson, Lindsay; Albers, Lisa; Becker, Ronald; Bridgemohan, Carolyn; Friedman, Sandra; Munir, Kerim; Nazir, Ramzi; Palfrey, Judith; Schonwald, Alison; Simmons, Esau; Rappaport, Leonard A.; Gauthier, Julie; Mottron, Laurent; Joober, Ridha; Rouleau, Guy; Rehnstrom, Karola; Von Wendt, Lennart; Peltonen, Leena.
In: Nature, Vol. 461, No. 7265, 08.10.2009, p. 802-808.Research output: Contribution to journal › Article
}
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
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
VL - 461
SP - 802
EP - 808
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7265
ER -