Genetics, Genome-Wide Association Studies, and Menarche

Abstract

Puberty is characterized by maturation of the hypothalamic–pituitary–gonadal axis, development of secondary sexual features, increased linear growth velocity, maturation of the epiphyses limiting additional growth, and achievement of menarche. The age at menarche appears to have a significant genetic component. With the advent of genome-wide association studies (GWASs), the genome has been interrogated to find associations between specific loci and age at menarche. It is apparent that multiple genetic loci, epigenetic mechanisms, and environmental factors modulate this biological event crucial for reproductive competence.

Keywords

age at menarche - puberty - GWAS - LIN28B

• References

• 1 Turcu A, Smith JM, Auchus R, Rainey WE. Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions. Compr Physiol 2014; 4 (4) 1369-1381
• 2 Rege J, Rainey WE. The steroid metabolome of adrenarche. J Endocrinol 2012; 214 (2) 133-143
• 3 Biro FM, Pinney SM, Huang B, Baker ER, Walt Chandler D, Dorn LD. Hormone changes in peripubertal girls. J Clin Endocrinol Metab 2014; 99 (10) 3829-3835
• 4 Ducharme JR, Forest MG, De Peretti E, Sempé M, Collu R, Bertrand J. Plasma adrenal and gonadal sex steroids in human pubertal development. J Clin Endocrinol Metab 1976; 42 (3) 468-476
• 5 Chumlea WC, Schubert CM, Roche AF , et al. Age at menarche and racial comparisons in US girls. Pediatrics 2003; 111 (1) 110-113
• 6 Cabrera SM, Bright GM, Frane JW, Blethen SL, Lee PA. Age of thelarche and menarche in contemporary US females: a cross-sectional analysis. J Pediatr Endocrinol Metab 2014; 27 (1–2) 47-51
• 7 Rosenfield RL. Clinical review: adolescent anovulation: maturational mechanisms and implications. J Clin Endocrinol Metab 2013; 98 (9) 3572-3583
• 8 Rapisarda JJ, Bergman KS, Steiner RA, Foster DL. Response to estradiol inhibition of tonic luteinizing hormone secretion decreases during the final stage of puberty in the rhesus monkey. Endocrinology 1983; 112 (4) 1172-1179
• 9 Treloar AE, Boynton RE, Behn BG, Brown BW. Variation of the human menstrual cycle through reproductive life. Int J Fertil 1967; 12 (1, Pt 2): 77-126
• 10 Diaz A, Laufer MR, Breech LL ; American Academy of Pediatrics Committee on Adolescence; American College of Obstetricians and Gynecologists Committee on Adolescent Health Care. Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Pediatrics 2006; 118 (5) 2245-2250
• 11 Legro RS, Lin HM, Demers LM, Lloyd T. Rapid maturation of the reproductive axis during perimenarche independent of body composition. J Clin Endocrinol Metab 2000; 85 (3) 1021-1025
• 12 Wray S. From nose to brain: development of gonadotrophin-releasing hormone-1 neurones. J Neuroendocrinol 2010; 22 (7) 743-753
• 13 Belchetz PE, Plant TM, Nakai Y, Keogh EJ, Knobil E. Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone. Science 1978; 202 (4368) 631-633
• 14 Ojeda SR, Skinner MR. Puberty in the rat. In: Neill JD, Plant TM, Pfaff DW, , et al., eds. Knobil and Neill's Physiology of Reproduction, 3rd edition. St Louis, MO: Academic Press/Elsevier; 2006: 2126-2061
• 15 Ojeda SR, Dubay C, Lomniczi A , et al. Gene networks and the neuroendocrine regulation of puberty. Mol Cell Endocrinol 2010; 324 (1–2) 3-11
• 16 Sharif A, Baroncini M, Prevot V. Role of glia in the regulation of gonadotropin-releasing hormone neuronal activity and secretion. Neuroendocrinology 2013; 98 (1) 1-15
• 17 Remmers F, Delemarre-van de Waal HA. Developmental programming of energy balance and its hypothalamic regulation. Endocr Rev 2011; 32 (2) 272-311
• 18 Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM. Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci U S A 2005; 102 (6) 2129-2134
• 19 Lehman MN, Coolen LM, Goodman RL. Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion. Endocrinology 2010; 151 (8) 3479-3489
• 20 Cheng G, Coolen LM, Padmanabhan V, Goodman RL, Lehman MN. The kisspeptin/neurokinin B/dynorphin (KNDy) cell population of the arcuate nucleus: sex differences and effects of prenatal testosterone in sheep. Endocrinology 2010; 151 (1) 301-311
• 21 Ramaswamy S, Guerriero KA, Gibbs RB, Plant TM. Structural interactions between kisspeptin and GnRH neurons in the mediobasal hypothalamus of the male rhesus monkey (Macaca mulatta) as revealed by double immunofluorescence and confocal microscopy. Endocrinology 2008; 149 (9) 4387-4395
• 22 Plant TM. Neuroendocrine control of the onset of puberty. Front Neuroendocrinol 2015; 38: 73-88
• 23 Skorupskaite K, George JT, Anderson RA. The kisspeptin-GnRH pathway in human reproductive health and disease. Hum Reprod Update 2014; 20 (4) 485-500
• 24 Lomniczi A, Wright H, Ojeda SR. Epigenetic regulation of female puberty. Front Neuroendocrinol 2015; 36: 90-107
• 25 Dissen GA, Lomniczi A, Heger S, Neff TL, Ojeda SR. Hypothalamic EAP1 (enhanced at puberty 1) is required for menstrual cyclicity in nonhuman primates. Endocrinology 2012; 153 (1) 350-361
• 26 Lomniczi A, Garcia-Rudaz C, Ramakrishnan R , et al. A single-nucleotide polymorphism in the EAP1 gene is associated with amenorrhea/oligomenorrhea in nonhuman primates. Endocrinology 2012; 153 (1) 339-349
• 27 Cukier P, Wright H, Rulfs T , et al. Molecular and gene network analysis of thyroid transcription factor 1 (TTF1) and enhanced at puberty (EAP1) genes in patients with GnRH-dependent pubertal disorders. Horm Res Paediatr 2013; 80 (4) 257-266
• 28 Meyer JM, Eaves LJ, Heath AC, Martin NG. Estimating genetic influences on the age-at-menarche: a survival analysis approach. Am J Med Genet 1991; 39 (2) 148-154
• 29 Towne B, Czerwinski SA, Demerath EW, Blangero J, Roche AF, Siervogel RM. Heritability of age at menarche in girls from the Fels Longitudinal Study. Am J Phys Anthropol 2005; 128 (1) 210-219
• 30 Jahanfar S, Lye MS, Krishnarajah IS. Genetic and environmental effects on age at menarche, and its relationship with reproductive health in twins. Indian J Hum Genet 2013; 19 (2) 245-250
• 31 Morris DH, Jones ME, Schoemaker MJ, Ashworth A, Swerdlow AJ. Familial concordance for age at menarche: analyses from the Breakthrough Generations Study. Paediatr Perinat Epidemiol 2011; 25 (3) 306-311
• 32 Kaprio J, Rimpelä A, Winter T, Viken RJ, Rimpelä M, Rose RJ. Common genetic influences on BMI and age at menarche. Hum Biol 1995; 67 (5) 739-753
• 33 Beneduzzi D, Trarbach EB, Min L , et al. Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay. Fertil Steril 2014; 102 (3) 838-846.e2
• 34 He C, Kraft P, Chasman DI , et al. A large-scale candidate gene association study of age at menarche and age at natural menopause. Hum Genet 2010; 128 (5) 515-527
• 35 Hagen CP, Sørensen K, Aksglaede L , et al. Pubertal onset in girls is strongly influenced by genetic variation affecting FSH action. Sci Rep 2014; 4: 6412
• 36 Silveira LG, Noel SD, Silveira-Neto AP , et al. Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab 2010; 95 (5) 2276-2280
• 37 Teles MG, Bianco SD, Brito VN , et al. A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med 2008; 358 (7) 709-715
• 38 Bianco SD, Vandepas L, Correa-Medina M , et al. KISS1R intracellular trafficking and degradation: effect of the Arg386Pro disease-associated mutation. Endocrinology 2011; 152 (4) 1616-1626
• 39 Abreu AP, Dauber A, Macedo DB , et al. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med 2013; 368 (26) 2467-2475
• 40 Abreu AP, Macedo DB, Brito VN, Kaiser UB, Latronico AC. A new pathway in the control of the initiation of puberty: the MKRN3 gene. J Mol Endocrinol 2015; 54 (3) R131-R139
• 41 Hagen CP, Sørensen K, Mieritz MG, Johannsen TH, Almstrup K, Juul A. Circulating MKRN3 levels decline prior to pubertal onset and through puberty: a longitudinal study of healthy girls. J Clin Endocrinol Metab 2015; 100 (5) 1920-1926
• 42 Delahanty RJ, Beeghly-Fadiel A, Long JR , et al. Evaluation of GWAS-identified genetic variants for age at menarche among Chinese women. Hum Reprod 2013; 28 (4) 1135-1143
• 43 He C, Kraft P, Chen C , et al. Genome-wide association studies identify loci associated with age at menarche and age at natural menopause. Nat Genet 2009; 41 (6) 724-728
• 44 Perry JR, Stolk L, Franceschini N , et al. Meta-analysis of genome-wide association data identifies two loci influencing age at menarche. Nat Genet 2009; 41 (6) 648-650
• 45 Ong KK, Elks CE, Li S , et al. Genetic variation in LIN28B is associated with the timing of puberty. Nat Genet 2009; 41 (6) 729-733
• 46 Sulem P, Gudbjartsson DF, Rafnar T , et al. Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche. Nat Genet 2009; 41 (6) 734-738
• 47 Tanikawa C, Okada Y, Takahashi A , et al. Genome wide association study of age at menarche in the Japanese population. PLoS ONE 2013; 8 (5) e63821
• 48 Cousminer DL, Stergiakouli E, Berry DJ , et al. Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty. Hum Mol Genet 2014; 23 (16) 4452-4464
• 49 Croteau-Chonka DC, Lange LA, Lee NR, Adair LS, Mohlke KL. Replication of LIN28B SNP association with age of menarche in young Filipino women. Pediatr Obes 2013; 8 (5) e50-e53
• 50 Widén E, Ripatti S, Cousminer DL , et al. Distinct variants at LIN28B influence growth in height from birth to adulthood. Am J Hum Genet 2010; 86 (5) 773-782
• 51 Leinonen JT, Surakka I, Havulinna AS , et al. Association of LIN28B with adult adiposity-related traits in females. PLoS ONE 2012; 7 (11) e48785
• 52 Carty CL, Spencer KL, Setiawan VW , et al. Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study. Hum Reprod 2013; 28 (6) 1695-1706
• 53 Demerath EW, Liu CT, Franceschini N , et al. Genome-wide association study of age at menarche in African-American women. Hum Mol Genet 2013; 22 (16) 3329-3346
• 54 Chen CT, Fernández-Rhodes L, Brzyski RG , et al. Replication of loci influencing ages at menarche and menopause in Hispanic women: the Women's Health Initiative SHARe Study. Hum Mol Genet 2012; 21 (6) 1419-1432
• 55 Perry JR, Day F, Elks CE , et al. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature 2014; 514 (7520) 92-97
• 56 Lunetta KL, Day FR, Sulem P , et al; EPIC-InterAct Consortium; Generation Scotland. Rare coding variants and X-linked loci associated with age at menarche. Nat Commun 2015; 6: 7756
• 57 Sangiao-Alvarellos S, Manfredi-Lozano M, Ruiz-Pino F , et al. Changes in hypothalamic expression of the Lin28/let-7 system and related microRNAs during postnatal maturation and after experimental manipulations of puberty. Endocrinology 2013; 154 (2) 942-955
• 58 Tommiska J, Wehkalampi K, Vaaralahti K, Laitinen EM, Raivio T, Dunkel L. LIN28B in constitutional delay of growth and puberty. J Clin Endocrinol Metab 2010; 95 (6) 3063-3066
• 59 Tommiska J, Sørensen K, Aksglaede L , et al. LIN28B, LIN28A, KISS1, and KISS1R in idiopathic central precocious puberty. BMC Res Notes 2011; 4: 363
• 60 Silveira-Neto AP, Leal LF, Emerman AB , et al. Absence of functional LIN28B mutations in a large cohort of patients with idiopathic central precocious puberty. Horm Res Paediatr 2012; 78 (3) 144-150
• 61 Euling SY, Herman-Giddens ME, Lee PA , et al. Examination of US puberty-timing data from 1940 to 1994 for secular trends: panel findings. Pediatrics 2008; 121 (Suppl. 03) S172-S191
• 62 Parent AS, Teilmann G, Juul A, Skakkebaek NE, Toppari J, Bourguignon JP. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr Rev 2003; 24 (5) 668-693
• 63 Garn SM, LaVelle M, Rosenberg KR, Hawthorne VM. Maturational timing as a factor in female fatness and obesity. Am J Clin Nutr 1986; 43 (6) 879-883
• 64 Biro FM, Khoury P, Morrison JA. Influence of obesity on timing of puberty. Int J Androl 2006; 29 (1) 272-277 , discussion 286–290
• 65 Lee JM, Appugliese D, Kaciroti N, Corwyn RF, Bradley RH, Lumeng JC. Weight status in young girls and the onset of puberty. Pediatrics 2007; 119 (3) e624-e630
• 66 Oh CM, Oh IH, Choi KS, Choe BK, Yoon TY, Choi JM. Relationship between body mass index and early menarche of adolescent girls in Seoul. J Prev Med Pub Health 2012; 45 (4) 227-234
• 67 Salgin B, Norris SA, Prentice P , et al. Even transient rapid infancy weight gain is associated with higher BMI in young adults and earlier menarche. Int J Obes 2015; 39 (6) 939-944
• 68 Soliman A, De Sanctis V, Elalaily R. Nutrition and pubertal development. Indian J Endocrinol Metab 2014; 18 (Suppl. 01) S39-S47
• 69 Day FR, Perry JR, Ong KK. Genetic regulation of puberty timing in humans. Neuroendocrinology 2015; 102 (4) 247-255
• 70 Farooqi S. Genetic strategies to understand physiological pathways regulating body weight. Mamm Genome 2014; 25 (9–10) 377-383
• 71 Tu W, Wagner EK, Eckert GJ , et al. Associations between menarche-related genetic variants and pubertal growth in male and female adolescents. J Adolesc Health 2015; 56 (1) 66-72
• 72 Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 2003; 348 (12) 1085-1095
• 73 Farooqi SI. Genetic, molecular and physiological mechanisms involved in human obesity: Society for Endocrinology Medal Lecture 2012. Clin Endocrinol (Oxf) 2015; 82 (1) 23-28
• 74 Godfrey KM, Inskip HM, Hanson MA. The long-term effects of prenatal development on growth and metabolism. Semin Reprod Med 2011; 29 (3) 257-265
• 75 Ong KK, Ahmed ML, Emmett PM, Preece MA, Dunger DB. Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. BMJ 2000; 320 (7240) 967-971
• 76 Ibáñez L, de Zegher F. Puberty after prenatal growth restraint. Horm Res 2006; 65 (Suppl. 03) 112-115
• 77 Thankamony A, Ong KK, Ahmed ML, Ness AR, Holly JM, Dunger DB. Higher levels of IGF-I and adrenal androgens at age 8 years are associated with earlier age at menarche in girls. J Clin Endocrinol Metab 2012; 97 (5) E786-E790
• 78 Dunger DB, Ahmed ML, Ong KK. Early and late weight gain and the timing of puberty. Mol Cell Endocrinol 2006; 254–255: 140-145
• 79 Ong KK, Northstone K, Wells JC , et al. Earlier mother's age at menarche predicts rapid infancy growth and childhood obesity. PLoS Med 2007; 4 (4) e132
• 80 Proos L, Gustafsson J. Is early puberty triggered by catch-up growth following undernutrition?. Int J Environ Res Public Health 2012; 9: 1791-1809
• 81 Henrichs KL, McCauley HL, Miller E, Styne DM, Saito N, Breslau J. Early menarche and childhood adversities in a nationally representative sample. Int J Pediatr Endocrinol 2014; 2014 (1) 14
• 82 Boynton-Jarrett R, Wright RJ, Putnam FW , et al. Childhood abuse and age at menarche. J Adolesc Health 2013; 52 (2) 241-247
• 83 Mueller NT, Jacobs Jr DR, MacLehose RF , et al. Consumption of caffeinated and artificially sweetened soft drinks is associated with risk of early menarche. Am J Clin Nutr 2015; 102 (3) 648-654
• 84 Carwile JL, Willett WC, Spiegelman D , et al. Sugar-sweetened beverage consumption and age at menarche in a prospective study of US girls. Hum Reprod 2015; 30 (3) 675-683
• 85 Segovia-Siapco G, Pribis P, Messina M, Oda K, Sabaté J. Is soy intake related to age at onset of menarche? A cross-sectional study among adolescents with a wide range of soy food consumption. Nutr J 2014; 13: 54
• 86 Rzeczkowska PA, Hou H, Wilson MD, Palmert MR. Epigenetics: a new player in the regulation of mammalian puberty. Neuroendocrinology 2014; 99 (3–4) 139-155
• 87 Lango Allen H, Estrada K, Lettre G , et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 2010; 467 (7317) 832-838
• 88 Lomniczi A, Wright H, Castellano JM , et al. Epigenetic regulation of puberty via zinc finger protein-mediated transcriptional repression. Nat Commun 2015; 6: 10195
• 89 Miller CA, Sweatt JD. Covalent modification of DNA regulates memory formation. Neuron 2007; 53 (6) 857-869
• 90 Gabory A, Attig L, Junien C. Developmental programming and epigenetics. Am J Clin Nutr 2011; 94 (6, Suppl): 1943S-1952S
• 91 Gong TT, Wang YL, Ma XX. Age at menarche and endometrial cancer risk: a dose-response meta-analysis of prospective studies. Sci Rep 2015; 5: 14051
• 92 Wang Z, Risch H, Lu L , et al. Joint effect of genotypic and phenotypic features of reproductive factors on endometrial cancer risk. Sci Rep 2015; 5: 15582
• 93 Bodicoat DH, Schoemaker MJ, Jones ME , et al. Timing of pubertal stages and breast cancer risk: the Breakthrough Generations Study. Breast Cancer Res 2014; 16 (1) R18
• 94 Velie EM, Nechuta S, Osuch JR. Lifetime reproductive and anthropometric risk factors for breast cancer in postmenopausal women. Breast Dis 2005; –2006; 24: 17-35
• 95 Glueck CJ, Morrison JA, Wang P, Woo JG. Early and late menarche are associated with oligomenorrhea and predict metabolic syndrome 26 years later. Metabolism 2013; 62 (11) 1597-1606
• 96 Dreyfus J, Jacobs Jr DR, Mueller N , et al. Age at menarche and cardiometabolic risk in adulthood: the Coronary Artery Risk Development in Young Adults Study. J Pediatr 2015; 167 (2) 344-52.e1
• 97 Widén E, Silventoinen K, Sovio U , et al. Pubertal timing and growth influences cardiometabolic risk factors in adult males and females. Diabetes Care 2012; 35 (4) 850-856
• 98 Naves M, Díaz-López JB, Gómez C, Rodríguez-Rebollar A, Cannata-Andía JB. Determinants of incidence of osteoporotic fractures in the female Spanish population older than 50. Osteoporos Int 2005; 16 (12) 2013-2017
• 99 Fujiwara S, Kasagi F, Yamada M, Kodama K. Risk factors for hip fracture in a Japanese cohort. J Bone Miner Res 1997; 12 (7) 998-1004
• 100 Chevalley T, Bonjour JP, Ferrari S, Rizzoli R. The influence of pubertal timing on bone mass acquisition: a predetermined trajectory detectable five years before menarche. J Clin Endocrinol Metab 2009; 94 (9) 3424-3431
• 101 Stamou MI, Cox KH, Crowley Jr WF. Discovering genes essential to the hypothalamic regulation of human reproduction using a human disease model: adjusting to life in the “-Omics” era. Endocr Rev 2015; 36 (6) 603-621
• 102 Guo Y, Shen H, Xiao P , et al. Genomewide linkage scan for quantitative trait loci underlying variation in age at menarche. J Clin Endocrinol Metab 2006; 91 (3) 1009-1014
• 103 Rothenbuhler A, Fradin D, Heath S , et al. Weight-adjusted genome scan analysis for mapping quantitative trait Loci for menarchal age. J Clin Endocrinol Metab 2006; 91 (9) 3534-3537
• 104 Pan F, Xiao P, Guo Y , et al. Chromosomal regions 22q13 and 3p25 may harbor quantitative trait loci influencing both age at menarche and bone mineral density. Hum Genet 2008; 123 (4) 419-427
• 105 Anderson CA, Zhu G, Falchi M , et al. A genome-wide linkage scan for age at menarche in three populations of European descent. J Clin Endocrinol Metab 2008; 93 (10) 3965-3970
• 106 Liu YZ, Guo YF, Wang L , et al. Genome-wide association analyses identify SPOCK as a key novel gene underlying age at menarche. PLoS Genet 2009; 5 (3) e1000420
• 107 Elks CE, Perry JR, Sulem P , et al. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. Nat Genet 2010; 42 (12) 1077-1085