A genome-wide association study of anorexia nervosa

V Boraska, C S Franklin, J A B Floyd, L M Thornton, L M Huckins, L Southam, N W Rayner, I Tachmazidou, K L Klump, J Treasure, C M Lewis, U Schmidt, F Tozzi, K Kiezebrink, J Hebebrand, P Gorwood, R A H Adan, M J H Kas, A Favaro, P Santonastaso & 31 others F Fernández-Aranda, M Gratacos, F Rybakowski, M Dmitrzak-Weglarz, J Kaprio, A Keski-Rahkonen, A Raevuori, E F Van Furth, M C T Slof-Op 't Landt, J I Hudson, T Reichborn-Kjennerud, G P S Knudsen, P Monteleone, A S Kaplan, A Karwautz, H Hakonarson, W H Berrettini, Y Guo, D Li, N J Schork, G Komaki, T Ando, H Inoko, T Esko, K Fischer, K Männik, A Metspalu, J H Baker, R D Cone, J Dackor, The Wellcome Trust Case Control Consortium 3

Research output: Contribution to journalArticle

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Abstract

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.Molecular Psychiatry advance online publication, 11 February 2014; doi:10.1038/mp.2013.187.

Original languageEnglish
Pages (from-to)1085-1094
Number of pages10
JournalMolecular Psychiatry
Volume19
Issue number10
Early online date11 Feb 2014
DOIs
Publication statusPublished - Oct 2014

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Genome-Wide Association Study
Anorexia Nervosa
Computer Simulation
Single Nucleotide Polymorphism
Psychiatry
Publications
Meta-Analysis
Japan
Body Weight
Observation
Genome
Datasets

Keywords

  • anorexia nervosa
  • body mass index
  • eating disorders
  • genome-wide association study
  • GWAS
  • metabolic

Cite this

Boraska, V., Franklin, C. S., Floyd, J. A. B., Thornton, L. M., Huckins, L. M., Southam, L., ... The Wellcome Trust Case Control Consortium 3 (2014). A genome-wide association study of anorexia nervosa. Molecular Psychiatry, 19(10), 1085-1094. https://doi.org/10.1038/mp.2013.187

A genome-wide association study of anorexia nervosa. / Boraska, V; Franklin, C S; Floyd, J A B; Thornton, L M; Huckins, L M; Southam, L; Rayner, N W; Tachmazidou, I; Klump, K L; Treasure, J; Lewis, C M; Schmidt, U; Tozzi, F; Kiezebrink, K; Hebebrand, J; Gorwood, P; Adan, R A H; Kas, M J H; Favaro, A; Santonastaso, P; Fernández-Aranda, F; Gratacos, M; Rybakowski, F; Dmitrzak-Weglarz, M; Kaprio, J; Keski-Rahkonen, A; Raevuori, A; Van Furth, E F; Slof-Op 't Landt, M C T; Hudson, J I; Reichborn-Kjennerud, T; Knudsen, G P S; Monteleone, P; Kaplan, A S; Karwautz, A; Hakonarson, H; Berrettini, W H; Guo, Y; Li, D; Schork, N J; Komaki, G; Ando, T; Inoko, H; Esko, T; Fischer, K; Männik, K; Metspalu, A; Baker, J H; Cone, R D; Dackor, J; The Wellcome Trust Case Control Consortium 3.

In: Molecular Psychiatry, Vol. 19, No. 10, 10.2014, p. 1085-1094.

Research output: Contribution to journalArticle

Boraska, V, Franklin, CS, Floyd, JAB, Thornton, LM, Huckins, LM, Southam, L, Rayner, NW, Tachmazidou, I, Klump, KL, Treasure, J, Lewis, CM, Schmidt, U, Tozzi, F, Kiezebrink, K, Hebebrand, J, Gorwood, P, Adan, RAH, Kas, MJH, Favaro, A, Santonastaso, P, Fernández-Aranda, F, Gratacos, M, Rybakowski, F, Dmitrzak-Weglarz, M, Kaprio, J, Keski-Rahkonen, A, Raevuori, A, Van Furth, EF, Slof-Op 't Landt, MCT, Hudson, JI, Reichborn-Kjennerud, T, Knudsen, GPS, Monteleone, P, Kaplan, AS, Karwautz, A, Hakonarson, H, Berrettini, WH, Guo, Y, Li, D, Schork, NJ, Komaki, G, Ando, T, Inoko, H, Esko, T, Fischer, K, Männik, K, Metspalu, A, Baker, JH, Cone, RD, Dackor, J & The Wellcome Trust Case Control Consortium 3 2014, 'A genome-wide association study of anorexia nervosa', Molecular Psychiatry, vol. 19, no. 10, pp. 1085-1094. https://doi.org/10.1038/mp.2013.187
Boraska V, Franklin CS, Floyd JAB, Thornton LM, Huckins LM, Southam L et al. A genome-wide association study of anorexia nervosa. Molecular Psychiatry. 2014 Oct;19(10):1085-1094. https://doi.org/10.1038/mp.2013.187
Boraska, V ; Franklin, C S ; Floyd, J A B ; Thornton, L M ; Huckins, L M ; Southam, L ; Rayner, N W ; Tachmazidou, I ; Klump, K L ; Treasure, J ; Lewis, C M ; Schmidt, U ; Tozzi, F ; Kiezebrink, K ; Hebebrand, J ; Gorwood, P ; Adan, R A H ; Kas, M J H ; Favaro, A ; Santonastaso, P ; Fernández-Aranda, F ; Gratacos, M ; Rybakowski, F ; Dmitrzak-Weglarz, M ; Kaprio, J ; Keski-Rahkonen, A ; Raevuori, A ; Van Furth, E F ; Slof-Op 't Landt, M C T ; Hudson, J I ; Reichborn-Kjennerud, T ; Knudsen, G P S ; Monteleone, P ; Kaplan, A S ; Karwautz, A ; Hakonarson, H ; Berrettini, W H ; Guo, Y ; Li, D ; Schork, N J ; Komaki, G ; Ando, T ; Inoko, H ; Esko, T ; Fischer, K ; Männik, K ; Metspalu, A ; Baker, J H ; Cone, R D ; Dackor, J ; The Wellcome Trust Case Control Consortium 3. / A genome-wide association study of anorexia nervosa. In: Molecular Psychiatry. 2014 ; Vol. 19, No. 10. pp. 1085-1094.
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AU - Rayner, N W

AU - Tachmazidou, I

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AU - Hudson, J I

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N2 - Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.Molecular Psychiatry advance online publication, 11 February 2014; doi:10.1038/mp.2013.187.

AB - Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.Molecular Psychiatry advance online publication, 11 February 2014; doi:10.1038/mp.2013.187.

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KW - body mass index

KW - eating disorders

KW - genome-wide association study

KW - GWAS

KW - metabolic

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