Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts

Mark O. Goodarzi, Michelle R. Jones, Xiaohui Li, Angela K. Chua, Obed A. Garcia, Yii Der I. Chen, Ronald M. Krauss, Jerome I. Rotter, Wendy Ankener, Richard S. Legro, Ricardo Azziz, Jerome F. Strauss, Andrea Dunaif, Margrit Urbanek

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Abstract

Background: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with a strong familial component. PCOS is characterised by hyperandrogenaemia and irregular menses. A recent genome-wide association study (GWAS) of PCOS in a Chinese cohort identified three reproducible PCOS susceptibility loci mapping to 2p16.3 (luteinising hormone/choriogonadotropin receptor; LHCGR), 2p21 (thyroid associated protein; THADA), and 9q33.3 (DENN/ MADD domain containing 1A; DENNDIA). The impact of these loci in non-Chinese PCOS cohorts remains to be determined. Methods and results: The study tested association with PCOS of seven single nucleotide polymorphisms mapping to the three Chinese PCOS loci in two European derived PCOS cohorts (cohort A = 939 cases and 957 controls; cohort B = 535 cases and 845 controls). Cases fulfilled the National Institute of Child Health & Human Development criteria for PCOS. Variation in DENND1A was strongly associated with PCOS in the study cohort (pcombined cohorts=10 -8); multiple variants in THADA were also associated with PCOS, while there was no significant evidence for association of LHCGR variation with PCOS. The present study had >80% power to detect an effect of similar size as was observed by Chen et al for DENND1A and THADA, but reduced power (at <40%) for LHCGR at p=0.0001. The study had sufficient power (57e88%) for LHCGR at p=0.01. Conclusions At least two of the PCOS susceptibility loci identified in the Chinese PCOS GWAS (DENND1A and THADA) are also associated with PCOS in European derived populations, and are therefore likely to be important in the aetiology of PCOS regardless of ethnicity. The analysis of the LHCGR gene was not sufficiently powered to detect modest effects.

Original languageEnglish (US)
Pages (from-to)90-95
Number of pages6
JournalJournal of Medical Genetics
Volume49
Issue number2
DOIs
StatePublished - Feb 1 2012

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Polycystic Ovary Syndrome
Genome-Wide Association Study
Nucleotide Mapping
LH Receptors
Menstruation
National Institutes of Health (U.S.)
Human Development
Chorionic Gonadotropin

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Goodarzi, M. O., Jones, M. R., Li, X., Chua, A. K., Garcia, O. A., Chen, Y. D. I., ... Urbanek, M. (2012). Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. Journal of Medical Genetics, 49(2), 90-95. https://doi.org/10.1136/jmedgenet-2011-100427

Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. / Goodarzi, Mark O.; Jones, Michelle R.; Li, Xiaohui; Chua, Angela K.; Garcia, Obed A.; Chen, Yii Der I.; Krauss, Ronald M.; Rotter, Jerome I.; Ankener, Wendy; Legro, Richard S.; Azziz, Ricardo; Strauss, Jerome F.; Dunaif, Andrea; Urbanek, Margrit.

In: Journal of Medical Genetics, Vol. 49, No. 2, 01.02.2012, p. 90-95.

Research output: Contribution to journalArticle

Goodarzi, MO, Jones, MR, Li, X, Chua, AK, Garcia, OA, Chen, YDI, Krauss, RM, Rotter, JI, Ankener, W, Legro, RS, Azziz, R, Strauss, JF, Dunaif, A & Urbanek, M 2012, 'Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts', Journal of Medical Genetics, vol. 49, no. 2, pp. 90-95. https://doi.org/10.1136/jmedgenet-2011-100427
Goodarzi, Mark O. ; Jones, Michelle R. ; Li, Xiaohui ; Chua, Angela K. ; Garcia, Obed A. ; Chen, Yii Der I. ; Krauss, Ronald M. ; Rotter, Jerome I. ; Ankener, Wendy ; Legro, Richard S. ; Azziz, Ricardo ; Strauss, Jerome F. ; Dunaif, Andrea ; Urbanek, Margrit. / Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. In: Journal of Medical Genetics. 2012 ; Vol. 49, No. 2. pp. 90-95.
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title = "Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts",
abstract = "Background: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with a strong familial component. PCOS is characterised by hyperandrogenaemia and irregular menses. A recent genome-wide association study (GWAS) of PCOS in a Chinese cohort identified three reproducible PCOS susceptibility loci mapping to 2p16.3 (luteinising hormone/choriogonadotropin receptor; LHCGR), 2p21 (thyroid associated protein; THADA), and 9q33.3 (DENN/ MADD domain containing 1A; DENNDIA). The impact of these loci in non-Chinese PCOS cohorts remains to be determined. Methods and results: The study tested association with PCOS of seven single nucleotide polymorphisms mapping to the three Chinese PCOS loci in two European derived PCOS cohorts (cohort A = 939 cases and 957 controls; cohort B = 535 cases and 845 controls). Cases fulfilled the National Institute of Child Health & Human Development criteria for PCOS. Variation in DENND1A was strongly associated with PCOS in the study cohort (pcombined cohorts=10 -8); multiple variants in THADA were also associated with PCOS, while there was no significant evidence for association of LHCGR variation with PCOS. The present study had >80{\%} power to detect an effect of similar size as was observed by Chen et al for DENND1A and THADA, but reduced power (at <40{\%}) for LHCGR at p=0.0001. The study had sufficient power (57e88{\%}) for LHCGR at p=0.01. Conclusions At least two of the PCOS susceptibility loci identified in the Chinese PCOS GWAS (DENND1A and THADA) are also associated with PCOS in European derived populations, and are therefore likely to be important in the aetiology of PCOS regardless of ethnicity. The analysis of the LHCGR gene was not sufficiently powered to detect modest effects.",
author = "Goodarzi, {Mark O.} and Jones, {Michelle R.} and Xiaohui Li and Chua, {Angela K.} and Garcia, {Obed A.} and Chen, {Yii Der I.} and Krauss, {Ronald M.} and Rotter, {Jerome I.} and Wendy Ankener and Legro, {Richard S.} and Ricardo Azziz and Strauss, {Jerome F.} and Andrea Dunaif and Margrit Urbanek",
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T1 - Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts

AU - Goodarzi, Mark O.

AU - Jones, Michelle R.

AU - Li, Xiaohui

AU - Chua, Angela K.

AU - Garcia, Obed A.

AU - Chen, Yii Der I.

AU - Krauss, Ronald M.

AU - Rotter, Jerome I.

AU - Ankener, Wendy

AU - Legro, Richard S.

AU - Azziz, Ricardo

AU - Strauss, Jerome F.

AU - Dunaif, Andrea

AU - Urbanek, Margrit

PY - 2012/2/1

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N2 - Background: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with a strong familial component. PCOS is characterised by hyperandrogenaemia and irregular menses. A recent genome-wide association study (GWAS) of PCOS in a Chinese cohort identified three reproducible PCOS susceptibility loci mapping to 2p16.3 (luteinising hormone/choriogonadotropin receptor; LHCGR), 2p21 (thyroid associated protein; THADA), and 9q33.3 (DENN/ MADD domain containing 1A; DENNDIA). The impact of these loci in non-Chinese PCOS cohorts remains to be determined. Methods and results: The study tested association with PCOS of seven single nucleotide polymorphisms mapping to the three Chinese PCOS loci in two European derived PCOS cohorts (cohort A = 939 cases and 957 controls; cohort B = 535 cases and 845 controls). Cases fulfilled the National Institute of Child Health & Human Development criteria for PCOS. Variation in DENND1A was strongly associated with PCOS in the study cohort (pcombined cohorts=10 -8); multiple variants in THADA were also associated with PCOS, while there was no significant evidence for association of LHCGR variation with PCOS. The present study had >80% power to detect an effect of similar size as was observed by Chen et al for DENND1A and THADA, but reduced power (at <40%) for LHCGR at p=0.0001. The study had sufficient power (57e88%) for LHCGR at p=0.01. Conclusions At least two of the PCOS susceptibility loci identified in the Chinese PCOS GWAS (DENND1A and THADA) are also associated with PCOS in European derived populations, and are therefore likely to be important in the aetiology of PCOS regardless of ethnicity. The analysis of the LHCGR gene was not sufficiently powered to detect modest effects.

AB - Background: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with a strong familial component. PCOS is characterised by hyperandrogenaemia and irregular menses. A recent genome-wide association study (GWAS) of PCOS in a Chinese cohort identified three reproducible PCOS susceptibility loci mapping to 2p16.3 (luteinising hormone/choriogonadotropin receptor; LHCGR), 2p21 (thyroid associated protein; THADA), and 9q33.3 (DENN/ MADD domain containing 1A; DENNDIA). The impact of these loci in non-Chinese PCOS cohorts remains to be determined. Methods and results: The study tested association with PCOS of seven single nucleotide polymorphisms mapping to the three Chinese PCOS loci in two European derived PCOS cohorts (cohort A = 939 cases and 957 controls; cohort B = 535 cases and 845 controls). Cases fulfilled the National Institute of Child Health & Human Development criteria for PCOS. Variation in DENND1A was strongly associated with PCOS in the study cohort (pcombined cohorts=10 -8); multiple variants in THADA were also associated with PCOS, while there was no significant evidence for association of LHCGR variation with PCOS. The present study had >80% power to detect an effect of similar size as was observed by Chen et al for DENND1A and THADA, but reduced power (at <40%) for LHCGR at p=0.0001. The study had sufficient power (57e88%) for LHCGR at p=0.01. Conclusions At least two of the PCOS susceptibility loci identified in the Chinese PCOS GWAS (DENND1A and THADA) are also associated with PCOS in European derived populations, and are therefore likely to be important in the aetiology of PCOS regardless of ethnicity. The analysis of the LHCGR gene was not sufficiently powered to detect modest effects.

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