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Cited by 504Hypothalamic control of reproductive hormonesGenetic Associations and EpidemiologyGenetic Mapping and Diversity in Plants and Animals

Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies

Open access
The GIANT Consortium, Elks, Cathy E, Perry, John R B, Sulem, Patrick, Chasman, Daniel I, Franceschini, Nora, He, Chunyan, Lunetta, Kathryn L +167 more·2010·Nature Genetics
DOI 10.1038/ng.714PMC PMC3140055
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Abstract

To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10−60) and 9q31.2 (P = 2.2 × 10−33), we identified 30 new menarche loci (all P < 5 × 10−8) and found suggestive evidence for a further 10 loci (P < 1.9 × 10−6). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.

AI snapshot

Written from the paper’s full text.

TL;DR

A large meta-analysis of 32 genome-wide association studies in 87,802 women of European descent identified 30 novel loci for age at menarche, in addition to confirming LIN28B and 9q31.2. The findings link menarche timing to energy homeostasis, hormonal regulation, and pathways including coenzyme A and fatty acid biosynthesis.

Key findings

  • The meta-analysis confirmed known loci at LIN28B (rs7759938; P=1.6×10−58) and 9q31.2 (rs2090409; P=4.4×10−33), and identified 30 novel menarche loci at genome-wide significance (all P<5×10−8), with suggestive evidence for 10 further loci (P<1.9×10−6).
  • Novel loci included four previously associated with BMI (in/near FTO, SEC16B, TRA2B, TMEM18), three in/near energy-homeostasis genes (BSX, CRTC1, MCHR2), and three in/near hormonal-regulation genes (INHBA, PCSK2, RXRG).
  • Per-allele effect sizes for novel loci ranged from 4.5 to 2.1 weeks per allele; among the four largest replication cohorts, all 42 known, confirmed, and possible novel loci explained 3.6% to 6.1% of variance in age at menarche.
  • Ingenuity and MAGENTA pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.

Methods

  • Stage 1 was a meta-analysis of 32 genome-wide association studies comprising 87,802 women of White European ancestry, with age at menarche restricted to 9–17 years and analyses adjusted for birth year.
  • Genotypes were imputed to ~2.5 million autosomal SNPs using HapMap CEU Build 35/36; each study performed additive-model association testing, results were genomic-control corrected, and inverse-variance fixed-effects meta-analysis was conducted in METAL.
  • Replication used in silico GWAS data from 16 additional studies and new genotyping in ALSPAC, totaling up to 14,731 women; conditional analysis, IPA, MAGENTA, eQTL, CNV, non-synonymous SNP, and candidate-gene assessments were also performed.

Limitations

  • The paper states that age at menarche was mostly recalled several years later and often to the nearest whole year; although recalled age is valid and unlikely to be systematically biased by genotype, non-differential error would reduce statistical power.
  • The paper states that causal variants were largely unidentified, many top SNPs were hundreds of kb from the nearest gene, and some loci contained several plausible genes; it also notes the study was restricted to European ancestry and not generalizable to other groups.
  • The paper states that the replication sample was substantially smaller than Stage 1 and underpowered to confirm individual SNP associations; it also notes that childhood growth/body-fatness data before menarche were unavailable in most studies, limiting causal inference about pleiotropy with body size.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/ng.714

Cites

90 of 90 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 38 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Ingenuity and MAGENTA pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.

    “Ingenuity and MAGENTA pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The nearest gene to each associated SNP is the relevant gene for functional interpretation.
  • Findingown data

    The meta-analysis found suggestive evidence for a further 10 loci (P<1.9×10−6).

    “found suggestive evidence for a further 10 loci (P<1.9×10−6)”
    Quote in the paperNot a substantial claim
  • Findingown data

    The meta-analysis identified 30 novel loci for age at menarche at genome-wide significance (P<5×10−8).

    “we identified 30 novel menarche loci (all P<5×10−8)”
    Quote in the paperSubstantial claim
  • Findingown data

    New menarche loci included three in/near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG).

    “three in/near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG)”
    Quote in the paperNot a substantial claim
  • Findingown data

    New menarche loci included four previously associated with BMI (in/near FTO, SEC16B, TRA2B and TMEM18).

    “New loci included four previously associated with BMI (in/near FTO, SEC16B, TRA2B and TMEM18)”
    Quote in the paperNot a substantial claim
  • May combine two claims. 33
  • Classified as probably not a substantial claim. 18

  • May combine two claims.

    Findingown data

    The second signal at 6q21 (rs314279) had a low minor allele frequency (6%) and was not present in many studies.

    “The second signal at 6q21 (rs314279) had a low minor allele frequency (MAF, 6%) and was not present in many studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The second strongest novel signal was rs466639 (P=1.3×10−13), intronic in RXRG.

    “The second strongest novel signal was for rs466639 (P=1.3×10−13); this SNP is intronic in RXRG”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Network 1 is related to Gene Expression, Cellular Growth and Proliferation, Cellular Function and Maintenance and covers a wide and non-specific range of biological pathways.

    “Network 1, related to “Gene Expression, Cellular Growth and Proliferation, Cellular Function and Maintenance”, covers a wide and non-specific range of biological pathways.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The nearest gene to each associated SNP is the relevant gene for functional interpretation.

  • May combine two claims.

    Findingown data

    Three novel menarche loci were found in/near further genes implicated in energy homeostasis and body weight in animal models: rs6589964 near BSX, rs10423674 intronic in CRTC1, and rs4840046 near MCHR2.

    “Three novel menarche loci were found in/near further genes implicated in the regulation of energy homeostasis and body weight in animal models: rs6589964 (P=1.9×10−12) lies ~18kb from BSX; rs10423674 (P=5.9×10−9) is intronic in CRTC1; and rs4840046 (P=2.4×10−8) lies ~160kb from MCHR2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Four novel loci for menarche were previously identified by GWA studies for adult BMI: rs9939609 (in/near FTO, P=3.1×10−8), rs633715 (SEC16B, P=2.1×10−8), rs2002675 (TRA2B, ETV5, P=1.2×10−9) and rs2947411 (TMEM18, P=1.7×10−8).

    “Four novel loci for menarche were previously identified by GWA studies for adult BMI18–20; these were rs9939609 (in/near FTO, P=3.1×10−8), rs633715 (SEC16B, P=2.1×10−8), rs2002675 (TRA2B, ETV5, P=1.2×10−9) and rs2947411 (TMEM18, P=1.7×10−8).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [18] Frayling, T.M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007). source

      Not checked in the free run.

    • cites [19] Thorleifsson, G. et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat. Genet. 41, 18–24 (2009). source

      Not checked in the free run.

    • cites [20] Willer, C.J. et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat. Genet. 41, 25–34 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Findingnone given

    In HapMap the r2 between the two chromosome 6 SNPs was 0.015, but D' was 1.0.

    “In HapMap the r2 between the two chr 6 SNPs was 0.015, but the D’ was 1.0.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    rs852069 (P=3.3×10−8) lies approximately 84kb from PCSK2.

    “rs852069 (P=3.3×10−8) lies ~84kb from PCSK2”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    A combined meta-analysis of Stage 1 and replication gave confirmatory evidence for 30 novel menarche loci, leaving 10 unconfirmed possible loci.

    “A combined meta-analysis of the more stringent 2nd GC corrected Stage 1 results and replication cohorts gave confirmatory evidence for 30 novel menarche loci, leaving 10 unconfirmed possible menarche loci”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The transcripts associated with these three variants were in GAB2 (rs10899489), RBM6 (rs6762477) and NARG2 (rs3743266).

    “These transcripts were in GAB2 (associated with rs10899489), RBM6 (rs6762477) and NARG2 (rs3743266)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    SNPs in the regions of TAC3R (top hit rs17034046; P=3.4×10−7) and ESR1 (top hit rs9383922; P=2.2×10−6) were significantly associated with age at menarche after correction for multiple testing.

    “SNPs in the regions of TAC3R (top hit: rs17034046; P=3.4×10−7, ~19kb upstream of TAC3R) and ESR1 (top hit: rs9383922; P=2.2×10−6, 110kb upstream of ESR1) were significantly associated with age at menarche after correction for multiple testing”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    rs7160413 (menarche P=2.2×10−5) is near DLK1, a gene implicated in early onset puberty.

    “rs7160413 (menarche P-value=2.2×10−5) is near DLK1, a gene implicated in early onset puberty29.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Temple, I.K., Shrubb, V., Lever, M., Bullman, H. & Mackay, D.J. Isolated imprinting mutation of the DLK1/GTL2 locus associated with a clinical presentation of maternal uniparental disomy of chromosome 14. J. Med. Genet. 44, 637–640 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    rs3101336 tags a CNV near the NEGR1 gene locus, which has been previously associated with body mass index.

    “This SNP tags a CNV near to the NEGR1 gene locus, which has been previously associated with body mass index20.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Willer, C.J. et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat. Genet. 41, 25–34 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Outside already associated regions, three non-synonymous SNPs were associated with age at menarche after Bonferroni correction: rs1254319 in C14orf39 (P=1.9×10−7), rs7653652 in C3orf38 (P=1.4×10−6) and rs913588 in JMJD2C (P=3.3×10−6).

    “Outside of the already associated regions, three ns-SNPs were associated with age at menarche after correction for multiple testing (Bonferroni threshold for 12,062 independent tests was P<4.1×10−6). These ns-SNPs were rs1254319 in C14orf39 (P=1.9×10−7), rs7653652 in C3orf38 (P=1.4×10−6) and rs913588 in JMJD2C (P=3.3×10−6).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In all cases the BMI- or WHR-increasing allele was associated with earlier menarche, consistent with the direction of association in epidemiological studies.

    “In all cases the BMI- or WHR-increasing allele was associated with earlier menarche, which is consistent with the direction of association in epidemiological studies35.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Onland-Moret, N.C. et al. Age at menarche in relation to adult height: the EPIC study. Am. J. Epidemiol. 162, 623–632 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Nine of the 12 BMI loci and 2 of the 4 WHR loci tested were associated with age at menarche.

    “Nine of the 12 BMI loci and 2 of the 4 WHR loci tested were associated with age at menarche”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Nine of the 42 menarche loci were associated with adult BMI (P<0.05; N=32,530); in all cases the allele associated with higher BMI was associated with earlier menarche.

    “Nine of the 42 menarche loci were associated with adult BMI (at P<0.05; N=32,530); in all cases the allele associated with higher BMI was associated with earlier menarche”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    rs10835211 (menarche P=9.4×10−6) is near BDNF, a BMI locus implicated in eating behavior and body weight regulation.

    “rs10835211 (menarche P-value=9.4×10−6) is near BDNF, which is a BMI locus and is implicated in eating behavior and body weight regulation27,28.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] Kernie, S.G., Liebl, D.J. & Parada, L.F. BDNF regulates eating behavior and locomotor activity in mice. EMBO J. 19, 1290–1300 (2000). source

      Not checked in the free run.

    • cites [28] Xu, B. et al. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat. Neurosci. 6, 736–742 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    None of the top signals represented non-synonymous SNPs, and only two were in LD with such variants (in OLFM2 and TRIM66).

    “Indeed, none of the top signals represented non-synonymous SNPs, and only two were in LD with such variants (in OLFM2 and TRIM66).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Several adult height-increasing alleles were also associated with age at menarche, but at different loci these alleles were associated with either earlier or later menarche.

    “We found that several adult height-increasing alleles were also associated with age at menarche (Table 3), but at different loci these alleles were associated with either earlier or later menarche.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Eighteen of the menarche loci were associated with adult height (P<0.05; N~130,000); for three of these the direction of effect was opposite to that predicted from epidemiological studies.

    “Eighteen of the menarche loci were associated with adult height (at P<0.05; N~130,000); although for three of these the direction of effect was opposite to that predicted from epidemiological studies”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among the confirmed novel menarche loci were several implicated in body weight regulation, including four loci with established associations with BMI.

    “Among the confirmed novel menarche loci were several loci implicated in body weight regulation, including four loci with established associations with BMI”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The menarche loci together explained between 3.6-6.1% of the variance in age at menarche, equivalent to 7.2-12.2% of its heritability.

    “Despite the large size of our meta-analysis and the substantial increase in the number of menarche loci, these together explained between 3.6–6.1% of the variance in age at menarche, equivalent to 7.2–12.2% of its heritability.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In a large GWAS meta-analysis comprising over 87,000 women, the authors identified 30 novel loci for the timing of menarche and provide evidence for a further 10 possible novel loci.

    “we identified 30 novel loci for the timing of menarche, and provide evidence for a further 10 possible novel loci.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In GIANT consortium data, no associations were detected between these loci and adult BMI, but the BSX and MCHR2 loci were nominally associated with adult height.

    “In the GIANT consortium data, we did not detect any associations between these loci and adult BMI however the BSX and MCHR2 loci were nominally associated with adult height.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Many of the strongest associated SNPs were located hundreds of kb distant to the nearest gene, and some menarche loci contained several plausible genes.

    “Many of the strongest associated SNPs were located 100’s of kb distant to the nearest gene, and some menarche loci contained several plausible genes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A second menarche locus was identified in an intergenic region at 9q31.2.

    “A second menarche locus was identified in an intergenic region at 9q31.28,10.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] He, C. et al. Genome-wide association studies identify loci associated with age at menarche and age at natural menopause. Nat. Genet. 41, 724–728 (2009). source

      Not checked in the free run.

    • cites [10] Perry, J.R. et al. Meta-analysis of genome-wide association data identifies two loci influencing age at menarche. Nat. Genet. 41, 648–650 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    The replication sample was substantially smaller than the Stage 1 sample and was underpowered to confirm individual SNP associations.

    “This replication sample was substantially smaller than our Stage 1 sample, and therefore underpowered to confirm individual SNP associations”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    PCSK2 differs from PCSK1 in that it additionally cleaves proluteinizing-hormone-releasing hormone and could therefore have a more direct influence on the reproductive hormone axis.

    “PCSK2 differs from PCSK1 in that it additionally cleaves proluteinizing-hormone-releasing hormone and could therefore have a more direct influence on the reproductive hormone axis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Rare deleterious mutations in TAC3R and its ligand TAC3 have been found in families affected by hypogonadotropic hypogonadism and pubertal failure.

    “Rare deleterious mutations in TAC3R, encoding a receptor for Neurokinin B, and in its ligand TAC3 have been found in families affected by hypogonadotropic hypogonadism and pubertal failure31.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Topaloglu, A.K. et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat. Genet. 41, 354–358 (2009). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ESR1 encodes an estrogen receptor essential for sexual development and reproductive function, and polymorphisms in ESR1 have previously been nominally associated with age at menarche.

    “ESR1 encodes an estrogen receptor that is essential for sexual development and reproductive function, and polymorphisms in ESR1 have previously been nominally associated with age at menarche33.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Stavrou, I., Zois, C., Ioannidis, J.P. & Tsatsoulis, A. Association of polymorphisms of the oestrogen receptor alpha gene with the age of menarche. Hum. Reprod. 17, 1101–1105 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The study was restricted to cohorts of European ancestry and its results are therefore not generalized to other groups.

    “Our study was restricted to cohorts of European ancestry and our results are therefore not generalized to other groups.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    African American girls tend to show earlier pubertal maturation compared to girls of White European ancestry.

    “African American girls tend to show earlier pubertal maturation compared to girls of White European ancestry42”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Herman-Giddens, M.E. et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics 99, 505–512 (1997). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Sufficient adiposity is required for maintenance of normal hypothalamic-pituitary-gonadal function, via signalling by adipocytokines such as leptin.

    “sufficient adiposity is also required for the maintenance of normal hypothalamic-pituitary-gonadal function, via signalling by adipocytokines such as leptin36.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Welt, C.K. et al. Recombinant human leptin in women with hypothalamic amenorrhea. N. Engl. J. Med. 351, 987–997 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The known menarche locus in LIN28B was shown to also influence the onset of breast development in girls, the timing of pubic hair development and voice breaking in boys, and the timing of the pubertal growth spurt in both boys and girls.

    “The known menarche locus in LIN28B was shown to also influence the onset of breast development in girls, the timing of pubic hair development and voice breaking in boys9, and the timing of the pubertal growth spurt in both boys and girls41.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Ong, K.K. et al. Genetic variation in LIN28B is associated with the timing of puberty. Nat. Genet. 41, 729–733 (2009). source

      Not checked in the free run.

    • cites [41] Widén, E. et al. Distinct variants at LIN28B influence growth in height from birth to adulthood. Am. J. Hum. Genet. 86, 773–782 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Earlier age at menarche is related to shorter adult stature in large epidemiological studies.

    “Earlier age at menarche is related to shorter adult stature in large epidemiological studies35.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Onland-Moret, N.C. et al. Age at menarche in relation to adult height: the EPIC study. Am. J. Epidemiol. 162, 623–632 (2005). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hypothalamic levels of long-chain fatty acyl-Coenzyme As have been shown to regulate rodent feeding behaviour and glucose homeostasis.

    “Hypothalamic levels of long-chain fatty acyl-Coenzyme As have been shown to regulate rodent feeding behaviour and glucose homeostasis37”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Pocai, A. et al. Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats. J. Clin. Invest. 116, 1081–1091 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Even the large meta-analysis would only have had sufficient power to detect half of true menarche SNPs with an effect size of 2 weeks per allele and MAF of 50%, and only 1 in 10 of those with MAF of 10%.

    “Assuming the presence of many true menarche SNPs with an effect size of 2 weeks per allele, even our large meta-analysis would only have had sufficient power to detect half of those SNPs with a MAF of 50%, and only 1 in 10 of those SNPs with MAF of 10% (Supplementary Fig. 8).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: There are many true menarche SNPs with an effect size of 2 weeks per allele.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Any non-differential error in recalled age at menarche would lead to reduced statistical power.

    “any non-differential error would lead to reduced statistical power.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    There are likely separate causal effects of rapid linear growth on earlier puberty, and of earlier pubertal maturation on earlier growth plate fusion and cessation of growth.

    “there are likely separate causal effects of rapid linear growth on earlier puberty, and of earlier pubertal maturation on earlier growth plate fusion and cessation of growth.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Significance in pathway analysis was determined when an individual pathway reached a false discovery rate (FDR) < 0.05.

    “Significance was determined when an individual pathway reached a false discovery rate (FDR) < 0.05 in either analysis (Supplementary table 9).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    As a quality control measure, non-genotyped SNPs with an imputation quality less than 0.3 (MACH) or 0.4 (IMPUTE) were excluded from the meta-analysis.

    “As a quality control measure, we excluded non-genotyped SNPs with an imputation quality less than 0.3 (for observed versus expected variance in MACH) or 0.4 (for IMPUTE’s proper info statistic) from the meta-analysis.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    In the replication analysis, only cohorts with >800 women were included in full model analyses, as smaller sample sizes may give spurious results.

    “We only included cohorts with >800 women in their full model analyses, as sample sizes smaller than this may give spurious results.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    A conditional analysis was carried out to establish whether genome-wide significant SNPs with low LD in the same chromosomal region were independent loci.

    “In order to establish whether genome-wide significant SNPs with low LD in the same chromosomal region (defined as r2<0.05 in a 750 kb region) were independent loci, we carried out a conditional analysis.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    In order to confirm possible novel menarche loci, the authors tested 42 top hits for in silico association with age at menarche in 8,669 women from 16 studies not included in the first stage meta-analysis.

    “In order to confirm our possible novel menarche loci, we tested our 42 top hits for in silico association with age at menarche in 8,669 women from 16 studies with GWAS data, and which were not included in the first stage meta-analysis (Supplementary Table 4).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Analyses were adjusted for birth year in order to remove the effect of the temporal decline in age at menarche.

    “Analyses were adjusted for birth year in order to remove the effect of the temporal decline in age at menarche.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Genotyping call rate cut-offs were at least 90% and SNPs were filtered for those with a minor allele frequency of greater than 1%.

    “Genotyping call rate cut-offs were at least 90% and SNPs were filtered for those with a minor allele frequency of greater than 1%.”
    Quote in the paperSubstantial claim
46 of 46

  • The paper relies on this without support.

    The nearest gene to each associated SNP is the relevant gene for functional interpretation.

    “The list of functions of those genes nearest to the menarche loci (Supplementary Table 7) and the results of pathway analyses indicate a wide diversity of biological processes that regulate the timing of female pubertal maturation.”

  • The paper relies on this without support.

    Recalled age at menarche is unlikely to show systematic bias by genotype.

    “and is unlikely to show systematic bias by genotype”

  • The authors state this as an assumption.

    There are many true menarche SNPs with an effect size of 2 weeks per allele.

    “Assuming the presence of many true menarche SNPs with an effect size of 2 weeks per allele”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The FTO locus has previously been reported to be associated with affected androgen levels, polycystic ovary syndrome susceptibility and age at menarche in females.

    “The FTO locus has previously been reported to be associated with affected androgen levels, polycystic ovary syndrome susceptibility and age at menarche in females while its impact on serum T and T-related diseases in men is unknown and warrants further investigations [46, 47].”

    From Causal relationship between obesity and serum testosterone status in men: A bi-directional mendelian randomization analysis (2017) · cites this paper as [46]

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Authors
The GIANT Consortium, Elks, C. E., Perry, J. R. B., Sulem, P., Chasman, D. I., Franceschini, N., He, C., Lunetta, K. L., Visser, J. A., Byrne, E. M., Cousminer, D. L., Gudbjartsson, D. F., Esko, T., Feenstra, B., Hottenga, J.-J., Koller, D. L., Kutalik, Z., Lin, P., Mangino, M., Marongiu, M., McArdle, P. F., Smith, A. V., Stolk, L., van Wingerden, S. H., Zhao, J. H., Albrecht, E., Corre, T., Ingelsson, E., Hayward, C., Magnusson, P. K. E., Smith, E. N., Ulivi, S., Warrington, N. M., Zgaga, L., Alavere, H., Amin, N., Aspelund, T., Bandinelli, S., Barroso, I., Berenson, G. S., Bergmann, S., Blackburn, H., Boerwinkle, E., Buring, J. E., Busonero, F., Campbell, H., Chanock, S. J., Chen, W., Cornelis, M. C., Couper, D., Coviello, A. D., d'Adamo, P., de Faire, U., de Geus, E. J. C., Deloukas, P., Döring, A., Smith, G. D., Easton, D. F., Eiriksdottir, G., Emilsson, V., Eriksson, J., Ferrucci, L., Folsom, A. R., Foroud, T., Garcia, M., Gasparini, P., Geller, F., Gieger, C., Gudnason, V., Hall, P., Hankinson, S. E., Ferreli, L., Heath, A. C., Hernandez, D. G., Hofman, A., Hu, F. B., Illig, T., Järvelin, M.-R., Johnson, A. D., Karasik, D., Khaw, K.-T., Kiel, D. P., Kilpeläinen, T. O., Kolcic, I., Kraft, P., Launer, L. J., Laven, J. S. E., Li, S., Liu, J., Levy, D., Martin, N. G., McArdle, W. L., Melbye, M., Mooser, V., Murray, J. C., Murray, S. S., Nalls, M. A., Navarro, P., Nelis, M., Ness, A. R., Northstone, K., Oostra, B. A., Peacock, M., Palmer, L. J., Palotie, A., Paré, G., Parker, A. N., Pedersen, N. L., Peltonen, L., Pennell, C. E., Pharoah, P., Polasek, O., Plump, A. S., Pouta, A., Porcu, E., Rafnar, T., Rice, J. P., Ring, S. M., Rivadeneira, F., Rudan, I., Sala, C., Salomaa, V., Sanna, S., Schlessinger, D., Schork, N. J., Scuteri, A., Segrè, A. V., Shuldiner, A. R., Soranzo, N., Sovio, U., Srinivasan, S. R., Strachan, D. P., Tammesoo, M.-L., Tikkanen, E., Toniolo, D., Tsui, K., Tryggvadottir, L., Tyrer, J., Uda, M., van Dam, R. M., van Meurs, J. B. J., Vollenweider, P., Waeber, G., Wareham, N. J., Waterworth, D. M., Weedon, M. N., Wichmann, H. E., Willemsen, G., Wilson, J. F., Wright, A. F., Young, L., Zhai, G., Zhuang, W. V., Bierut, L. J., Boomsma, D. I., Boyd, H. A., Crisponi, L., Demerath, E. W., van Duijn, C. M., Econs, M. J., Harris, T. B., Hunter, D. J., Loos, R. J. F., Metspalu, A., Montgomery, G. W., Ridker, P. M., Spector, T. D., Streeten, E. A., Stefansson, K., Thorsteinsdottir, U., Uitterlinden, A. G., Widen, E., Murabito, J. M., Ong, K. K., & Murray, A.
Affiliations
  • Addenbrooke's Hospital (GB)
  • University of Exeter (GB)
  • deCODE Genetics (Iceland) (IS)
  • Brigham and Women's Hospital (US)
  • University of North Carolina at Chapel Hill (US)
  • Indiana University Melvin and Bren Simon Comprehensive Cancer Center (US)
  • Boston University (US)
  • Erasmus MC (NL)
  • The University of Queensland (AU)
  • University of Helsinki (FI)
  • Estonian Biocentre (EE)
  • Statens Serum Institut (DK)
  • Vrije Universiteit Amsterdam (NL)
  • Indiana University Indianapolis (US)
  • SIB Swiss Institute of Bioinformatics (CH)
  • Washington University in St. Louis (US)
  • King's College London (GB)
  • National Research Council (IT)
  • University of Maryland, Baltimore (US)
  • University of Iceland (IS)
  • Helmholtz Munich (DE)
  • IRCCS Ospedale San Raffaele (IT)
  • Karolinska Institutet (SE)
  • Western General Hospital (GB)
  • Scripps Research Institute (US)
  • University of Trieste (IT)
  • The University of Western Australia (AU)
  • University of Edinburgh (GB)
  • Azienda Sanitaria di Firenze (IT)
  • Wellcome Sanger Institute (GB)
  • Tulane University (US)
  • The University of Texas Health Science Center at Houston (US)
  • National Institutes of Health (US)
  • Harvard University (US)
  • University of Bristol (GB)
  • University of Cambridge (GB)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
  • National Institute on Aging (US)
  • University of Minnesota (US)
  • Imperial College London (GB)
  • National Heart, Lung, and Blood Institute (US)
  • Genome Institute of Singapore (SG)
  • QIMR Berghofer Medical Research Institute (AU)
  • GlaxoSmithKline (United States) (US)
  • University of Iowa (US)
  • Indiana University School of Medicine (US)
  • Broad Institute (US)
  • Amgen (United States) (US)
  • Finnish Institute for Health and Welfare (FI)
  • University of Split (HR)
  • Istituti di Ricovero e Cura a Carattere Scientifico (IT)
  • St George's, University of London (GB)
  • University of Tartu (EE)
Corresponding author
  • Murabito, Joanne M
  • Ong, Ken K
  • Murray, Anna
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2010-11-21
Volume
42
Issue
12
Pages
1077-1085
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.714
PMC
PMC3140055
OpenAlex
W2082947145
Semantic Scholar
c9a098da9c8ec9c91dc9e45de5338e37cdb81638
Cited by
504
References
90
Citations by year
2026: 8 · 2025: 16 · 2024: 20 · 2023: 18 · 2022: 27 · 2021: 22 · 2020: 35 · 2019: 30 · 2018: 31 · 2017: 37 · 2016: 39 · 2015: 42 · 2014: 42 · 2013: 60 · 2012: 47
FWCI
6.05
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
  • PubMed Central (acceptedVersion)
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  • SERVAL (Université de Lausanne) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
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  • National Science Foundation (N01-HC-25195, 33CSCO-122661)
  • Juvenile Diabetes Research Foundation International (068545/Z/02)
  • March of Dimes Foundation
  • American Heart Association (0855082E, N01-HC-25195, N01-HC-55020, N01-HC-55018, N01-HC-55022, N01-HC-55019, N01-HC-55021, N01-HC-55015, N01-HC-55016)
  • Amgen
  • GlaxoSmithKline (33CSCO-122661)
  • Compagnia di San Paolo
  • Wellcome Trust (068545/Z/02), 076467, G0000934, 89061/Z/09/Z, 068545, 129680, 077016/Z/05/Z, 079895, 076467/Z05/z, 205419)
  • Scottish Government
  • Cancer Research UK (10119, 10118, A10124, 11022, 10124, A10119)
  • European Commission (QLG2-CT-2002-01254, 245536, 018947, SF0180142s08, G0500539, 230374, 201550, 201413, 201865, LSHM‐CT‐2003‐503041, 205419, 01254, CA63464, CA54281, 212111, LSHG-CT-2006-018947)
  • University of Bristol (ICS110.1/RF97.71, 076467, 076467/Z/05/Z)
  • National Research Foundation (129494)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (116323, 55018, 122661, 55015, 33CSCO, 25195, 205419, 35627, 230374, 3100AO-116323/1, 3100AO, 201413, 129494, 212111, 166067, 120315, G0500539, 55016)
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  • National Institutes of Health (n01ag50002-3-0-0, n01ag12100-57-0-2, n01hc055019-025, 35627, n01hc055020-025, G0000934, 389875, 5u01hg004423-02, n01hc055016-027, 6r01hl087679-03, n01hc055021-036, n01hc055018-026, n01hc055015-031, ERC 230374, EU/QLRT-2001-01254, 8ul1tr000109-05, 068545/Z/02, n02hl64278-6-0-0, n01hc025195-11-0-0, 5r01hl043851-10, n01ag12109-11-0-0, QLG2-CT-2002-01254, 079895, n01hc055022-025, DK-072488, N01-HC55020, N01-HC-55021, N01-HC-55019, N01-HC-55022, N01-HC 25195, N01-HC55016, N01-HC55018, CA089392, CA40356, CA54281, CA63464, N01-HC-55015, HL69757)
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  • National Institute on Aging (N01-HC-55021, N.1‐AG‐1‐2111, N01-AG-12109, R03AG050002, P01AG025204, ICS 110.1/RF97.71, N01-AG012100, N.1-AG-1-1, R01AR/AG 41398, AG16592, N02-HL-6-4278, N01-HC-25195, N01 AG012109, 0855082E, N01-HC-55018, P01AG18397, R21AG032598, N01 AG050002, N01-HC-55015, N01-HC-55019, N01-HC-55020, R01AG016592, N01-HC-55016, R01AG041517, P01AG018397, N01 AG-5-0002, N01-HC-55022)
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  • National Center for Advancing Translational Sciences (UL1-TR000109)
  • National Institute on Minority Health and Health Disparities (263MD9164, 263MD 821336, R01MD009164)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R03HD061437, HD061437)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords
age at menarche, puberty timing, genetic loci, body mass index, FTO, SEC16B, TMEM18, energy homeostasis, hormonal regulation, coenzyme A biosynthesis, fatty acid synthesis
MeSH terms
Adolescent, Aging, Body Height, Child, Female, Humans, Menarche, Obesity, Time Factors, Reproducibility of Results, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Inheritance Patterns, Quantitative Trait Loci, Body Size, Genome-Wide Association Study, Genetic Loci, DNA Copy Number Variations

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

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