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Genome wide association study of age at menarche in the Japanese population.

Tanikawa C, Okada Y, Takahashi A, Oda K, Kamatani N, Kubo M, Nakamura Y, Matsuda K - PLoS ONE (2013)

Bottom Line: Here, we identified an association between SNP (single nucleotide polymorphism) rs364663 at the LIN28B locus and AAM, with a P-value of 5.49×10(-7) and an effect size of 0.089 (year).We also evaluated 33 SNPs that were previously reported to be associated with AAM in women of European ancestry.Among them, two SNPs rs4452860 and rs7028916 in TMEM38B indicated significant association with AAM in the same directions as reported in previous studies (P = 0.0013 with an effect size of 0.051) even after Bonferroni correction for the 33 SNPs.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

ABSTRACT
Age at menarche (AAM) is a complex trait involving both genetic and environmental factors. To identify the genetic factors associated with AAM, we conducted a large-scale meta-analysis of genome-wide association studies using more than 15,000 Japanese female samples. Here, we identified an association between SNP (single nucleotide polymorphism) rs364663 at the LIN28B locus and AAM, with a P-value of 5.49×10(-7) and an effect size of 0.089 (year). We also evaluated 33 SNPs that were previously reported to be associated with AAM in women of European ancestry. Among them, two SNPs rs4452860 and rs7028916 in TMEM38B indicated significant association with AAM in the same directions as reported in previous studies (P = 0.0013 with an effect size of 0.051) even after Bonferroni correction for the 33 SNPs. In addition, six loci in or near CCDC85A, LOC100421670, CA10, ZNF483, ARNTL, and RXRG exhibited suggestive association with AAM (P<0.05). Our findings elucidated the impact of genetic variations on AAM in the Japanese population.

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Results from meta-analysis of four genome-wide association studies.A total of 15,495 female samples were analyzed in this study.
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pone-0063821-g001: Results from meta-analysis of four genome-wide association studies.A total of 15,495 female samples were analyzed in this study.

Mentions: The associations of these imputed SNPs with AAM were evaluated using a linear regression model [30] and meta-analysis. Quantile-Quantile plots of P-values indicated the Inflation factors to be as low as 1.039 (Figure 1), suggesting no substantial population stratification existed in our study population. Although we could not identify significant association that satisfied the genome-wide significant threshold (P<5×10−8), SNP rs364663 which is located within intron 2 of the LIN28B gene at 6q21 indicated the strongest association with a P-value of 5.49×10−7 (Table 2, Figure 2). SNP rs364663 exhibited the association with AAM in all four cohorts without significant heterogeneity in both effect sizes and directions (P-value for heterogeneity = 0.29; Table 3), suggesting that the observed associations at LIN28B are not the result of false-positives due to study-specific bias. Regional p-value plots indicated that all of the AMM-associated SNPs were clustered around the LIN28B locus (Figure 2). Previously reported SNPs rs314263 and rs7759938 near the LIN28B locus 21,24 also associated with AAM (P = 1.03×10−6 and 1.12×10−6, respectively) in the same direction. In addition to the 6q21 locus, 17 SNPs in seven genomic regions exhibited suggestive association with a p-value of<1×10−5 (Table 2). To further investigate the physiological role of these loci, the associations of these variations with body mass index (BMI) and height were evaluated using previously published results in 26,620 Japanese subjects [31]. SNP rs9404590 near the LIN28B locus associated with height with p-value of 0.0003 (Table S2), but we did not find significant association (P<0.01) between these loci and BMI (Table S2).


Genome wide association study of age at menarche in the Japanese population.

Tanikawa C, Okada Y, Takahashi A, Oda K, Kamatani N, Kubo M, Nakamura Y, Matsuda K - PLoS ONE (2013)

Results from meta-analysis of four genome-wide association studies.A total of 15,495 female samples were analyzed in this study.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3646805&req=5

pone-0063821-g001: Results from meta-analysis of four genome-wide association studies.A total of 15,495 female samples were analyzed in this study.
Mentions: The associations of these imputed SNPs with AAM were evaluated using a linear regression model [30] and meta-analysis. Quantile-Quantile plots of P-values indicated the Inflation factors to be as low as 1.039 (Figure 1), suggesting no substantial population stratification existed in our study population. Although we could not identify significant association that satisfied the genome-wide significant threshold (P<5×10−8), SNP rs364663 which is located within intron 2 of the LIN28B gene at 6q21 indicated the strongest association with a P-value of 5.49×10−7 (Table 2, Figure 2). SNP rs364663 exhibited the association with AAM in all four cohorts without significant heterogeneity in both effect sizes and directions (P-value for heterogeneity = 0.29; Table 3), suggesting that the observed associations at LIN28B are not the result of false-positives due to study-specific bias. Regional p-value plots indicated that all of the AMM-associated SNPs were clustered around the LIN28B locus (Figure 2). Previously reported SNPs rs314263 and rs7759938 near the LIN28B locus 21,24 also associated with AAM (P = 1.03×10−6 and 1.12×10−6, respectively) in the same direction. In addition to the 6q21 locus, 17 SNPs in seven genomic regions exhibited suggestive association with a p-value of<1×10−5 (Table 2). To further investigate the physiological role of these loci, the associations of these variations with body mass index (BMI) and height were evaluated using previously published results in 26,620 Japanese subjects [31]. SNP rs9404590 near the LIN28B locus associated with height with p-value of 0.0003 (Table S2), but we did not find significant association (P<0.01) between these loci and BMI (Table S2).

Bottom Line: Here, we identified an association between SNP (single nucleotide polymorphism) rs364663 at the LIN28B locus and AAM, with a P-value of 5.49×10(-7) and an effect size of 0.089 (year).We also evaluated 33 SNPs that were previously reported to be associated with AAM in women of European ancestry.Among them, two SNPs rs4452860 and rs7028916 in TMEM38B indicated significant association with AAM in the same directions as reported in previous studies (P = 0.0013 with an effect size of 0.051) even after Bonferroni correction for the 33 SNPs.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

ABSTRACT
Age at menarche (AAM) is a complex trait involving both genetic and environmental factors. To identify the genetic factors associated with AAM, we conducted a large-scale meta-analysis of genome-wide association studies using more than 15,000 Japanese female samples. Here, we identified an association between SNP (single nucleotide polymorphism) rs364663 at the LIN28B locus and AAM, with a P-value of 5.49×10(-7) and an effect size of 0.089 (year). We also evaluated 33 SNPs that were previously reported to be associated with AAM in women of European ancestry. Among them, two SNPs rs4452860 and rs7028916 in TMEM38B indicated significant association with AAM in the same directions as reported in previous studies (P = 0.0013 with an effect size of 0.051) even after Bonferroni correction for the 33 SNPs. In addition, six loci in or near CCDC85A, LOC100421670, CA10, ZNF483, ARNTL, and RXRG exhibited suggestive association with AAM (P<0.05). Our findings elucidated the impact of genetic variations on AAM in the Japanese population.

Show MeSH