Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa

L. M. Huckins; K. Hatzikotoulas; L. Southam; L. M. Thornton; J. Steinberg; F. Aguilera-Mckay; J. Treasure; U. Schmidt; C. Gunasinghe; A. Romero; C. Curtis; D. Rhodes; J. Moens; G. Kalsi; D. Dempster; R. Leung; A. Keohane; R. Burghardt; S. Ehrlich; J. Hebebrand; A. Hinney; A. Ludolph; E. Walton; P. Deloukas; A. Hofman; A. Palotie; P. Palta; F. J.A. van Rooij; K. Stirrups; R. A.H. Adan; C. Boni; R. Cone; G. Dedoussis; E. F. Furth; F. Gonidakis; P. Gorwood; J. Hudson; J. Kaprio; M. Kas; A. Keski-Rahonen; K. Kiezebrink; G. P.S. Knudsen; M. C.T. Slof-Op 'T Landt; M. Maj; A. M. Monteleone; P. Monteleone; A. H. Raevuori; T. Reichborn-Kjennerud; F. Tozzi; A. Tsitsika; A. A. Elburg; Eating Disorders Working Group of the Psychiatric Genomics Consortium; D. A. Collier; P. F. Sullivan; G. Breen; C. M. Bulik; E. Zeggini; S. Cohen-Woods

doi:10.1038/mp.2017.88

Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa

L. M. Huckins, K. Hatzikotoulas, L. Southam, L. M. Thornton, J. Steinberg, F. Aguilera-Mckay, J. Treasure, U. Schmidt, C. Gunasinghe, A. Romero, C. Curtis, D. Rhodes, J. Moens, G. Kalsi, D. Dempster, R. Leung, A. Keohane, R. Burghardt, S. Ehrlich, J. HebebrandA. Hinney, A. Ludolph, E. Walton, P. Deloukas, A. Hofman, A. Palotie, P. Palta, F. J.A. van Rooij, K. Stirrups, R. A.H. Adan, C. Boni, R. Cone, G. Dedoussis, E. F. Furth, F. Gonidakis, P. Gorwood, J. Hudson, J. Kaprio, M. Kas, A. Keski-Rahonen, K. Kiezebrink, G. P.S. Knudsen, M. C.T. Slof-Op 'T Landt, M. Maj, A. M. Monteleone, P. Monteleone, A. H. Raevuori, T. Reichborn-Kjennerud, F. Tozzi, A. Tsitsika, A. A. Elburg, Eating Disorders Working Group of the Psychiatric Genomics Consortium, D. A. Collier, P. F. Sullivan, G. Breen, C. M. Bulik, E. Zeggini, S. Cohen-Woods

College of Education, Psychology and Social Work

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Abstract

Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10 -6), and rs7700147, an intergenic variant (P=2.93 × 10 -5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.

Original language	English
Pages (from-to)	1169-1180
Number of pages	12
Journal	MOLECULAR PSYCHIATRY
Volume	23
Issue number	5
DOIs	https://doi.org/10.1038/mp.2017.88
Publication status	Published - 1 May 2018

Keywords

Genetics
molecular biology
anorexia nervosa

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Huckins, L. M., Hatzikotoulas, K., Southam, L., Thornton, L. M., Steinberg, J., Aguilera-Mckay, F., Treasure, J., Schmidt, U., Gunasinghe, C., Romero, A., Curtis, C., Rhodes, D., Moens, J., Kalsi, G., Dempster, D., Leung, R., Keohane, A., Burghardt, R., Ehrlich, S., ... Cohen-Woods, S. (2018). Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa. MOLECULAR PSYCHIATRY, 23(5), 1169-1180. https://doi.org/10.1038/mp.2017.88

@article{478687a250d94ee2b9c7aba5653499e4,

title = "Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa",

abstract = "Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10 -6), and rs7700147, an intergenic variant (P=2.93 × 10 -5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.",

keywords = "Genetics, molecular biology, anorexia nervosa",

author = "Huckins, {L. M.} and K. Hatzikotoulas and L. Southam and Thornton, {L. M.} and J. Steinberg and F. Aguilera-Mckay and J. Treasure and U. Schmidt and C. Gunasinghe and A. Romero and C. Curtis and D. Rhodes and J. Moens and G. Kalsi and D. Dempster and R. Leung and A. Keohane and R. Burghardt and S. Ehrlich and J. Hebebrand and A. Hinney and A. Ludolph and E. Walton and P. Deloukas and A. Hofman and A. Palotie and P. Palta and {van Rooij}, {F. J.A.} and K. Stirrups and Adan, {R. A.H.} and C. Boni and R. Cone and G. Dedoussis and Furth, {E. F.} and F. Gonidakis and P. Gorwood and J. Hudson and J. Kaprio and M. Kas and A. Keski-Rahonen and K. Kiezebrink and Knudsen, {G. P.S.} and {Slof-Op 'T Landt}, {M. C.T.} and M. Maj and Monteleone, {A. M.} and P. Monteleone and Raevuori, {A. H.} and T. Reichborn-Kjennerud and F. Tozzi and A. Tsitsika and Elburg, {A. A.} and {Eating Disorders Working Group of the Psychiatric Genomics Consortium} and Collier, {D. A.} and Sullivan, {P. F.} and G. Breen and Bulik, {C. M.} and E. Zeggini and L. Alfredsson and T. Ando and Andreassen, {O. A.} and H. Aschauer and Baker, {J. H.} and Barrett, {J. C.} and V. Bencko and Bergen, {A. W.} and Berrettini, {W. H.} and A. Birgeg{\aa}rd and Perica, {V. Boraska} and H. Brandt and L. Carlberg and M. Cassina and S. Cichon and M. Clementi and S. Cohen-Woods and J. Coleman and P. Courtet and S. Crawford and S. Crow and J. Crowley and Danner, {U. N.} and Davis, {O. S.P.} and M. Zwaan and D. Degortes and Desocio, {J. E.} and Dick, {D. M.} and D. Dikeos and C. Dina and B. Ding and M. Dmitrzak-Weglarz and E. Docampo and L. Duncan and K. Egberts and G. Escaram{\'i}s and T. Esko and T. Espeseth and X. Estivill and A. Favaro and F. Fern{\'a}ndez-Aranda and Fichter, {M. M.} and C. Finan and K. Fischer and Floyd, {J. A.B.} and L. Foretova and M. Forzan and Franklin, {C. S.} and S. Gallinger and G. Gambaro and Gaspar, {H. A.} and I. Giegling and M. Gratacos and S. Guillaume and Y. Guo and H. Hakonarson and Halmi, {K. A.} and J. Hauser and S. Helder and S. Herms and B. Herpertz-Dahlmann and W. Herzog and Hilliard, {C. E.} and C. H{\"u}bel and J. Huemer and H. Inoko and V. Janout and S. Jim{\'e}nez-Murcia and C. Johnson and A. Juli{\`a} and A. Jur{\'e}us and D. Kaminska and Kaplan, {A. S.} and L. Karhunen and A. Karwautz and W. Kaye and Kennedy, {J. L.} and L. Klareskog and Klump, {K. L.} and Koeleman, {B. P.C.} and D. Koubek and Via, {MC C.L.} and M. Land{\'e}n and Hellard, {S. Le} and Levitan, {R. D.} and D. Li and P. Lichtenstein and L. Lilenfeld and J. Lissowska and A. Lundervold and P. Magistretti and K. Mannik and S. Marsal and N. Martin and M. Mattingsdal and S. McDevitt and P. McGuffin and E. Merl and A. Metspalu and I. Meulenbelt and N. Micali and J. Mitchell and K. Mitchell and P. Mortensen and Munn-Chernoff, {M. A.} and M. Navratilova and I. Nilsson and C. Norring and I. Ntalla and Ophoff, {R. A.} and O'toole, {J. K.} and J. Pantel and H. Papezova and D. Pinto and R. Rabionet and A. Rajewski and N. Ramoz and Rayner, {N. W.} and S. Ripatti and M. Roberts and A. Rotondo and D. Rujescu and F. Rybakowski and P. Santonastaso and A. Scherag and Scherer, {S. W.} and Schork, {N. J.} and A. Schosser and L. Slachtova and R. Sladek and Slagboom, {P. E.} and A. Slopien and N. Soranzo and Steen, {V. M.} and E. Strengman and M. Strober and Szatkiewicz, {J. P.} and N. Szeszenia-Dabrowska and I. Tachmazidou and E. Tenconi and A. Tortorella and K. Tziouvas and G. Wagner and H. Watson and Wichmann, {H. E.} and E. Widen and Woodside, {D. B.} and J. Yanovski and S. Yao and Z. Yilmaz and S. Zerwas and S. Zipfel",

year = "2018",

month = may,

day = "1",

doi = "10.1038/mp.2017.88",

language = "English",

volume = "23",

pages = "1169--1180",

journal = "MOLECULAR PSYCHIATRY",

issn = "1359-4184",

publisher = "Nature",

number = "5",

}

Huckins, LM, Hatzikotoulas, K, Southam, L, Thornton, LM, Steinberg, J, Aguilera-Mckay, F, Treasure, J, Schmidt, U, Gunasinghe, C, Romero, A, Curtis, C, Rhodes, D, Moens, J, Kalsi, G, Dempster, D, Leung, R, Keohane, A, Burghardt, R, Ehrlich, S, Hebebrand, J, Hinney, A, Ludolph, A, Walton, E, Deloukas, P, Hofman, A, Palotie, A, Palta, P, van Rooij, FJA, Stirrups, K, Adan, RAH, Boni, C, Cone, R, Dedoussis, G, Furth, EF, Gonidakis, F, Gorwood, P, Hudson, J, Kaprio, J, Kas, M, Keski-Rahonen, A, Kiezebrink, K, Knudsen, GPS, Slof-Op 'T Landt, MCT, Maj, M, Monteleone, AM, Monteleone, P, Raevuori, AH, Reichborn-Kjennerud, T, Tozzi, F, Tsitsika, A, Elburg, AA, Eating Disorders Working Group of the Psychiatric Genomics Consortium, Collier, DA, Sullivan, PF, Breen, G, Bulik, CM, Zeggini, E & Cohen-Woods, S 2018, 'Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa', MOLECULAR PSYCHIATRY, vol. 23, no. 5, pp. 1169-1180. https://doi.org/10.1038/mp.2017.88

TY - JOUR

T1 - Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa

AU - Huckins, L. M.

AU - Hatzikotoulas, K.

AU - Southam, L.

AU - Thornton, L. M.

AU - Steinberg, J.

AU - Aguilera-Mckay, F.

AU - Treasure, J.

AU - Schmidt, U.

AU - Gunasinghe, C.

AU - Romero, A.

AU - Curtis, C.

AU - Rhodes, D.

AU - Moens, J.

AU - Kalsi, G.

AU - Dempster, D.

AU - Leung, R.

AU - Keohane, A.

AU - Burghardt, R.

AU - Ehrlich, S.

AU - Hebebrand, J.

AU - Hinney, A.

AU - Ludolph, A.

AU - Walton, E.

AU - Deloukas, P.

AU - Hofman, A.

AU - Palotie, A.

AU - Palta, P.

AU - van Rooij, F. J.A.

AU - Stirrups, K.

AU - Adan, R. A.H.

AU - Boni, C.

AU - Cone, R.

AU - Dedoussis, G.

AU - Furth, E. F.

AU - Gonidakis, F.

AU - Gorwood, P.

AU - Hudson, J.

AU - Kaprio, J.

AU - Kas, M.

AU - Keski-Rahonen, A.

AU - Kiezebrink, K.

AU - Knudsen, G. P.S.

AU - Slof-Op 'T Landt, M. C.T.

AU - Maj, M.

AU - Monteleone, A. M.

AU - Monteleone, P.

AU - Raevuori, A. H.

AU - Reichborn-Kjennerud, T.

AU - Tozzi, F.

AU - Tsitsika, A.

AU - Elburg, A. A.

AU - Eating Disorders Working Group of the Psychiatric Genomics Consortium

AU - Collier, D. A.

AU - Sullivan, P. F.

AU - Breen, G.

AU - Bulik, C. M.

AU - Zeggini, E.

AU - Alfredsson, L.

AU - Ando, T.

AU - Andreassen, O. A.

AU - Aschauer, H.

AU - Baker, J. H.

AU - Barrett, J. C.

AU - Bencko, V.

AU - Bergen, A. W.

AU - Berrettini, W. H.

AU - Birgegård, A.

AU - Perica, V. Boraska

AU - Brandt, H.

AU - Carlberg, L.

AU - Cassina, M.

AU - Cichon, S.

AU - Clementi, M.

AU - Cohen-Woods, S.

AU - Coleman, J.

AU - Courtet, P.

AU - Crawford, S.

AU - Crow, S.

AU - Crowley, J.

AU - Danner, U. N.

AU - Davis, O. S.P.

AU - Zwaan, M.

AU - Degortes, D.

AU - Desocio, J. E.

AU - Dick, D. M.

AU - Dikeos, D.

AU - Dina, C.

AU - Ding, B.

AU - Dmitrzak-Weglarz, M.

AU - Docampo, E.

AU - Duncan, L.

AU - Egberts, K.

AU - Escaramís, G.

AU - Esko, T.

AU - Espeseth, T.

AU - Estivill, X.

AU - Favaro, A.

AU - Fernández-Aranda, F.

AU - Fichter, M. M.

AU - Finan, C.

AU - Fischer, K.

AU - Floyd, J. A.B.

AU - Foretova, L.

AU - Forzan, M.

AU - Franklin, C. S.

AU - Gallinger, S.

AU - Gambaro, G.

AU - Gaspar, H. A.

AU - Giegling, I.

AU - Gratacos, M.

AU - Guillaume, S.

AU - Guo, Y.

AU - Hakonarson, H.

AU - Halmi, K. A.

AU - Hauser, J.

AU - Helder, S.

AU - Herms, S.

AU - Herpertz-Dahlmann, B.

AU - Herzog, W.

AU - Hilliard, C. E.

AU - Hübel, C.

AU - Huemer, J.

AU - Inoko, H.

AU - Janout, V.

AU - Jiménez-Murcia, S.

AU - Johnson, C.

AU - Julià, A.

AU - Juréus, A.

AU - Kaminska, D.

AU - Kaplan, A. S.

AU - Karhunen, L.

AU - Karwautz, A.

AU - Kaye, W.

AU - Kennedy, J. L.

AU - Klareskog, L.

AU - Klump, K. L.

AU - Koeleman, B. P.C.

AU - Koubek, D.

AU - Via, MC C.L.

AU - Landén, M.

AU - Hellard, S. Le

AU - Levitan, R. D.

AU - Li, D.

AU - Lichtenstein, P.

AU - Lilenfeld, L.

AU - Lissowska, J.

AU - Lundervold, A.

AU - Magistretti, P.

AU - Mannik, K.

AU - Marsal, S.

AU - Martin, N.

AU - Mattingsdal, M.

AU - McDevitt, S.

AU - McGuffin, P.

AU - Merl, E.

AU - Metspalu, A.

AU - Meulenbelt, I.

AU - Micali, N.

AU - Mitchell, J.

AU - Mitchell, K.

AU - Mortensen, P.

AU - Munn-Chernoff, M. A.

AU - Navratilova, M.

AU - Nilsson, I.

AU - Norring, C.

AU - Ntalla, I.

AU - Ophoff, R. A.

AU - O'toole, J. K.

AU - Pantel, J.

AU - Papezova, H.

AU - Pinto, D.

AU - Rabionet, R.

AU - Rajewski, A.

AU - Ramoz, N.

AU - Rayner, N. W.

AU - Ripatti, S.

AU - Roberts, M.

AU - Rotondo, A.

AU - Rujescu, D.

AU - Rybakowski, F.

AU - Santonastaso, P.

AU - Scherag, A.

AU - Scherer, S. W.

AU - Schork, N. J.

AU - Schosser, A.

AU - Slachtova, L.

AU - Sladek, R.

AU - Slagboom, P. E.

AU - Slopien, A.

AU - Soranzo, N.

AU - Steen, V. M.

AU - Strengman, E.

AU - Strober, M.

AU - Szatkiewicz, J. P.

AU - Szeszenia-Dabrowska, N.

AU - Tachmazidou, I.

AU - Tenconi, E.

AU - Tortorella, A.

AU - Tziouvas, K.

AU - Wagner, G.

AU - Watson, H.

AU - Wichmann, H. E.

AU - Widen, E.

AU - Woodside, D. B.

AU - Yanovski, J.

AU - Yao, S.

AU - Yilmaz, Z.

AU - Zerwas, S.

AU - Zipfel, S.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10 -6), and rs7700147, an intergenic variant (P=2.93 × 10 -5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.

AB - Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10 -6), and rs7700147, an intergenic variant (P=2.93 × 10 -5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.

KW - Genetics

KW - molecular biology

KW - anorexia nervosa

UR - http://www.scopus.com/inward/record.url?scp=85029816710&partnerID=8YFLogxK

U2 - 10.1038/mp.2017.88

DO - 10.1038/mp.2017.88

M3 - Article

C2 - 29155802

AN - SCOPUS:85029816710

SN - 1359-4184

VL - 23

SP - 1169

EP - 1180

JO - MOLECULAR PSYCHIATRY

JF - MOLECULAR PSYCHIATRY

IS - 5

ER -

Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa

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