Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia. / Harold, Denise; Connolly, Siobhan; Riley, Brien P.; Kendler, Kenneth S.; McCarthy, Shane E.; McCombie, William R.; Richards, Alex; Owen, Michael J.; O'Donovan, Michael C.; Walters, James; Donnelly, Peter; Bates, Lesley; Barroso, Ines; Blackwell, Jenefer M.; Bramon, Elvira; Brown, Matthew A.; Casas, Juan P.; Corvin, Aiden; Deloukas, Panos; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S.; Mathew, Christopher G.; Palmer, Colin N.A.; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J.; Trembath, Richard C.; Viswanathan, Ananth C.; Wood, Nicholas W.; Spencer, Chris C.A.; Band, Gavin; Bellenguez, Céline; Freeman, Colin; Hellenthal, Garrett; Giannoulatou, Eleni; Hopkins, Lucinda; Pirinen, Matti; Pearson, Richard; Strange, Amy; Su, Zhan; Vukcevic, Damjan; Pers, Tune H.; Hansen, Mark; Hansen, Thomas; Li, Tao; Olsen, Line; Pantelis, Christos; Rasmussen, Henrik B.; Werge, Thomas; Wellcome Trust Case Control Consortium 2; Schizophrenia Working Group of the Psychiatric Genomics Consortium.

In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, Vol. 180, No. 3, 2019, p. 223-231.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Harold, D, Connolly, S, Riley, BP, Kendler, KS, McCarthy, SE, McCombie, WR, Richards, A, Owen, MJ, O'Donovan, MC, Walters, J, Donnelly, P, Bates, L, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Hopkins, L, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Pers, TH, Hansen, M, Hansen, T, Li, T, Olsen, L, Pantelis, C, Rasmussen, HB, Werge, T, Wellcome Trust Case Control Consortium 2 & Schizophrenia Working Group of the Psychiatric Genomics Consortium 2019, 'Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia', American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, vol. 180, no. 3, pp. 223-231. https://doi.org/10.1002/ajmg.b.32716

APA

Harold, D., Connolly, S., Riley, B. P., Kendler, K. S., McCarthy, S. E., McCombie, W. R., Richards, A., Owen, M. J., O'Donovan, M. C., Walters, J., Donnelly, P., Bates, L., Barroso, I., Blackwell, J. M., Bramon, E., Brown, M. A., Casas, J. P., Corvin, A., Deloukas, P., ... Schizophrenia Working Group of the Psychiatric Genomics Consortium (2019). Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia. American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, 180(3), 223-231. https://doi.org/10.1002/ajmg.b.32716

Vancouver

Harold D, Connolly S, Riley BP, Kendler KS, McCarthy SE, McCombie WR et al. Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia. American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics. 2019;180(3):223-231. https://doi.org/10.1002/ajmg.b.32716

Author

Harold, Denise ; Connolly, Siobhan ; Riley, Brien P. ; Kendler, Kenneth S. ; McCarthy, Shane E. ; McCombie, William R. ; Richards, Alex ; Owen, Michael J. ; O'Donovan, Michael C. ; Walters, James ; Donnelly, Peter ; Bates, Lesley ; Barroso, Ines ; Blackwell, Jenefer M. ; Bramon, Elvira ; Brown, Matthew A. ; Casas, Juan P. ; Corvin, Aiden ; Deloukas, Panos ; Duncanson, Audrey ; Jankowski, Janusz ; Markus, Hugh S. ; Mathew, Christopher G. ; Palmer, Colin N.A. ; Plomin, Robert ; Rautanen, Anna ; Sawcer, Stephen J. ; Trembath, Richard C. ; Viswanathan, Ananth C. ; Wood, Nicholas W. ; Spencer, Chris C.A. ; Band, Gavin ; Bellenguez, Céline ; Freeman, Colin ; Hellenthal, Garrett ; Giannoulatou, Eleni ; Hopkins, Lucinda ; Pirinen, Matti ; Pearson, Richard ; Strange, Amy ; Su, Zhan ; Vukcevic, Damjan ; Pers, Tune H. ; Hansen, Mark ; Hansen, Thomas ; Li, Tao ; Olsen, Line ; Pantelis, Christos ; Rasmussen, Henrik B. ; Werge, Thomas ; Wellcome Trust Case Control Consortium 2 ; Schizophrenia Working Group of the Psychiatric Genomics Consortium. / Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia. In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics. 2019 ; Vol. 180, No. 3. pp. 223-231.

Bibtex

@article{00e6997e2b8346d8b7248c64f559ded4,
title = "Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia",
abstract = "Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.",
keywords = "GWAS, IBD mapping, rare variants",
author = "Denise Harold and Siobhan Connolly and Riley, {Brien P.} and Kendler, {Kenneth S.} and McCarthy, {Shane E.} and McCombie, {William R.} and Alex Richards and Owen, {Michael J.} and O'Donovan, {Michael C.} and James Walters and Peter Donnelly and Lesley Bates and Ines Barroso and Blackwell, {Jenefer M.} and Elvira Bramon and Brown, {Matthew A.} and Casas, {Juan P.} and Aiden Corvin and Panos Deloukas and Audrey Duncanson and Janusz Jankowski and Markus, {Hugh S.} and Mathew, {Christopher G.} and Palmer, {Colin N.A.} and Robert Plomin and Anna Rautanen and Sawcer, {Stephen J.} and Trembath, {Richard C.} and Viswanathan, {Ananth C.} and Wood, {Nicholas W.} and Spencer, {Chris C.A.} and Gavin Band and C{\'e}line Bellenguez and Colin Freeman and Garrett Hellenthal and Eleni Giannoulatou and Lucinda Hopkins and Matti Pirinen and Richard Pearson and Amy Strange and Zhan Su and Damjan Vukcevic and Pers, {Tune H.} and Mark Hansen and Thomas Hansen and Tao Li and Line Olsen and Christos Pantelis and Rasmussen, {Henrik B.} and Thomas Werge and {Wellcome Trust Case Control Consortium 2} and {Schizophrenia Working Group of the Psychiatric Genomics Consortium}",
year = "2019",
doi = "10.1002/ajmg.b.32716",
language = "English",
volume = "180",
pages = "223--231",
journal = "American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics",
issn = "1552-4841",
publisher = "JohnWiley & Sons, Inc.",
number = "3",

}

RIS

TY - JOUR

T1 - Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia

AU - Harold, Denise

AU - Connolly, Siobhan

AU - Riley, Brien P.

AU - Kendler, Kenneth S.

AU - McCarthy, Shane E.

AU - McCombie, William R.

AU - Richards, Alex

AU - Owen, Michael J.

AU - O'Donovan, Michael C.

AU - Walters, James

AU - Donnelly, Peter

AU - Bates, Lesley

AU - Barroso, Ines

AU - Blackwell, Jenefer M.

AU - Bramon, Elvira

AU - Brown, Matthew A.

AU - Casas, Juan P.

AU - Corvin, Aiden

AU - Deloukas, Panos

AU - Duncanson, Audrey

AU - Jankowski, Janusz

AU - Markus, Hugh S.

AU - Mathew, Christopher G.

AU - Palmer, Colin N.A.

AU - Plomin, Robert

AU - Rautanen, Anna

AU - Sawcer, Stephen J.

AU - Trembath, Richard C.

AU - Viswanathan, Ananth C.

AU - Wood, Nicholas W.

AU - Spencer, Chris C.A.

AU - Band, Gavin

AU - Bellenguez, Céline

AU - Freeman, Colin

AU - Hellenthal, Garrett

AU - Giannoulatou, Eleni

AU - Hopkins, Lucinda

AU - Pirinen, Matti

AU - Pearson, Richard

AU - Strange, Amy

AU - Su, Zhan

AU - Vukcevic, Damjan

AU - Pers, Tune H.

AU - Hansen, Mark

AU - Hansen, Thomas

AU - Li, Tao

AU - Olsen, Line

AU - Pantelis, Christos

AU - Rasmussen, Henrik B.

AU - Werge, Thomas

AU - Wellcome Trust Case Control Consortium 2

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium

PY - 2019

Y1 - 2019

N2 - Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.

AB - Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.

KW - GWAS

KW - IBD mapping

KW - rare variants

U2 - 10.1002/ajmg.b.32716

DO - 10.1002/ajmg.b.32716

M3 - Journal article

C2 - 30801977

AN - SCOPUS:85061993948

VL - 180

SP - 223

EP - 231

JO - American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics

JF - American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics

SN - 1552-4841

IS - 3

ER -

ID: 260352324