Genetic markers of ovarian follicle number and menopause in women of multiple ethnicities.
Oocyte loss has a significant impact on fertility and somatic health. Yet, we know little about factors that impact this process. We sought to identify genetic variants associated with ovarian reserve (oocyte number as measured by antral follicle count, AFC). Based on recently published genome-wide scans that identified loci associated with age of menopause, we also sought to test our hypothesis that follicle number and menopausal age share underlying genetic associations. We analyzed menopause-related variants for association with follicle number in an independent population of approximately 450 reproductive-aged women of European and African ancestry; these women were assessed for AFC, anthropometric, clinical, and lifestyle factors. One SNP strongly associated with later menopausal age in Caucasian women (+1.07 ± 0.11 years) in previous work was also associated with higher follicle counts in Caucasians (+2.79 ± 1.67 follicles) in our study. This variant is within the Minichromosome Maintenance Complex Component 8 (MCM8) gene, which we found was expressed within oocytes in follicles of the human ovary. In genome-wide scans of AFC, we also identified one marginally genome-wide and several nominally significant SNPs within several other genes associated with follicle number in both ethnic groups. Further, there were overlapping variants associated with multiple ovarian reserve markers (AFC, serum hormone levels, menopausal age). This study provides the first evidence for direct genetic associations underlying both follicle number and menopause and identifies novel candidate genes. Genetic variants associated with ovarian reserve may facilitate discovery of genetic markers to predict reproductive health and lifespan in women.
Department of Obstetrics and Gynecology, Institute for Stem Cell Biology and Regenerative Medicine, Center for Human Embryonic Stem Cell Research and Education, School of Medicine, Stanford University, 265 Campus Drive, Lorry I. Lokey Stem Cell Research Building Rm G1165, Stanford, CA 94305, USA. sonyas1@stanford.edu
Sonya M
SM
Schuh-Huerta
Nicholas A
NA
Johnson
Mitchell P
MP
Rosen
Barbara
B
Sternfeld
Marcelle I
MI
Cedars
Renee A
RA
Reijo Pera
D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000375:Aging / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics*; D005260:Female; D005298:Fertility / Q000502:physiology*; D005819:Genetic Markers; D006801:Humans; D008593:Menopause; D064110:Minichromosome Maintenance Proteins; D006080:Ovarian Follicle / Q000166:cytology* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044465:White People / Q000235:genetics*
D018797:Cell Cycle Proteins; D005819:Genetic Markers; C471623:MCM8 protein, human; D064110:Minichromosome Maintenance Proteins