BMI-associated alleles do not constitute risk alleles for polycystic ovary syndrome independently of BMI: a case-control study.
BACKGROUND
Polycystic Ovary Syndrome (PCOS) has a strong genetic background and the majority of patients with PCOS have elevated BMI levels. The aim of this study was to determine to which extent BMI-increasing alleles contribute to risk of PCOS when contemporaneous BMI is taken into consideration.


METHODS
Patients with PCOS and controls were recruited from the United Kingdom (563 cases and 791 controls) and The Netherlands (510 cases and 2720 controls). Cases and controls were of similar BMI. SNPs mapping to 12 BMI-associated loci which have been extensively replicated across different ethnicities, i.e., BDNF, FAIM2, ETV5, FTO, GNPDA2, KCTD15, MC4R, MTCH2, NEGR1, SEC16B, SH2B1, and TMEM18, were studied in association with PCOS within each cohort using the additive genetic model followed by a combined analysis. A genetic allelic count risk score model was used to determine the risk of PCOS for individuals carrying increasing numbers of BMI-increasing alleles.


RESULTS
None of the genetic variants, including FTO and MC4R, was associated with PCOS independently of BMI in the meta-analysis. Moreover, no differences were observed between cases and controls in the number of BMI-risk alleles present and no overall trend across the risk score groups was observed.


CONCLUSIONS
In this combined analysis of over 4,000 BMI-matched individuals from the United Kingdom and the Netherlands, we observed no association of BMI risk alleles with PCOS independent of BMI.
Department of Obstetrics and Gynecology, Subdivision of Reproductive Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Yvonne V
YV
Louwers
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom ; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
Nigel W
NW
Rayner
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Blanca M
BM
Herrera
Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Lisette
L
Stolk
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom ; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
Christopher J
CJ
Groves
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
Thomas M
TM
Barber
Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands ; Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Andre G
AG
Uitterlinden
Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London, United Kingdom.
Stephen
S
Franks
Department of Obstetrics and Gynecology, Subdivision of Reproductive Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Joop S E
JS
Laven
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom ; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
Mark I
MI
McCarthy
D000483:Alleles; D015992:Body Mass Index; D001835:Body Weight / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D009426:Netherlands; D009765:Obesity / Q000235:genetics; D050177:Overweight / Q000235:genetics; D011085:Polycystic Ovary Syndrome / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment / Q000379:methods / Q000706:statistics & numerical data; D012307:Risk Factors; D006113:United Kingdom