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Environmental and genetic contributors to salivary testosterone levels in infants.

Xia K, Yu Y, Ahn M, Zhu H, Zou F, Gilmore JH, Knickmeyer RC - Front Endocrinol (Lausanne) (2014)

Bottom Line: The top hit in males was rs10923844, an SNP of unknown function located downstream of HSD3B1 and HSD3B2.The top hits in females were two SNPs located upstream of ESR1 (rs3407085 and rs2295190).RF analysis, which reflects joint and conditional effects of multiple variants, indicated that genes involved in regulation of reproductive function, particularly LHCGR, are related to salivary testosterone levels in male infants, as are genes involved in cholesterol production, transport, and removal, while genes involved in estrogen signaling are related to salivary testosterone levels in female infants.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of North Carolina at Chapel Hill , Chapel Hill, NC , USA.

ABSTRACT
Transient activation of the hypothalamic-pituitary-gonadal axis in early infancy plays an important role in male genital development and sexual differentiation of the brain, but factors contributing to individual variation in testosterone levels during this period are poorly understood. We measured salivary testosterone levels in 222 infants (119 males, 103 females, 108 singletons, 114 twins) between 2.70 and 4.80 months of age. We tested 16 major demographic and medical history variables for effects on inter-individual variation in salivary testosterone. Using the subset of twins, we estimated genetic and environmental contributions to salivary testosterone levels. Finally, we tested single nucleotide polymorphisms (SNPs) within ±5 kb of genes involved in testosterone synthesis, transport, signaling, and metabolism for associations with salivary testosterone using univariate tests and random forest (RF) analysis. We report an association between 5 min APGAR scores and salivary testosterone levels in males. Twin modeling indicated that individual variability in testosterone levels was primarily explained by environmental factors. Regarding genetic variation, univariate tests did not reveal any variants significantly associated with salivary testosterone after adjusting for false discovery rate. The top hit in males was rs10923844, an SNP of unknown function located downstream of HSD3B1 and HSD3B2. The top hits in females were two SNPs located upstream of ESR1 (rs3407085 and rs2295190). RF analysis, which reflects joint and conditional effects of multiple variants, indicated that genes involved in regulation of reproductive function, particularly LHCGR, are related to salivary testosterone levels in male infants, as are genes involved in cholesterol production, transport, and removal, while genes involved in estrogen signaling are related to salivary testosterone levels in female infants.

No MeSH data available.


Correlation between effect sizes in full samples [correcting for log(10)transferrin] and subsamples with transferrin levels <0.50 mg/dl.
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Figure 4: Correlation between effect sizes in full samples [correcting for log(10)transferrin] and subsamples with transferrin levels <0.50 mg/dl.

Mentions: In males, no SNPs were significantly associated with salivary testosterone levels after adjusting for FDR in the full sample. The most significant association was for rs10923844, a variant of unknown function located downstream of HSD3B1 and HSD3B2 (adjusted p-value = 0.07, unadjusted p = 0.0002). This same SNP had an unadjusted p-value of 0.02 in the subsample of males with transferrin <0.50 mg/dl. Effect sizes for this variant were highly similar in the total male sample [adjusting for log(10)transferrin] and the subsample of males with transferrin <0.50 mg/dl (Beta = 6.26 and 6.02, respectively). Indeed, effect sizes for the full male sample are highly similar to the corresponding effect sizes in the subset of males with transferrin <0.50 mg/dl (see Figure 4). None of the previous GWAS hits for serum testosterone levels in adult males were significantly associated with salivary testosterone in infant males before or after adjusting for FDR in either the full sample or the subset of males with transferrin <0.50 mg/dl. In females, no SNPs were significantly associated with salivary testosterone levels after adjusting for FDR. The most significant associations were for two SNPs located upstream of ESR1 (rs3407085 and rs2295190) within the intron region of SYNE1 (spectrin repeat containing, nuclear envelope (1); adjusted and unadjusted p-values were 0.09 and 0.0004 for both variants (these variants are in complete linkage disequilibrium within our sample). Both variants had an unadjusted p-value of 0.04 in the subsample of females with transferrin <0.50 mg/dl. Effect sizes were highly similar for the total female sample [adjusting for log(10)transferrin] and the subsample of females with transferrin <0.50 mg/dl (Beta = −13.7 and −11.2, respectively), though we note that effect sizes for the full female sample do not correspond as well to the effect sizes in the reduced sample as compared to males (See Figure 4). Full results are available as supplemental data. Power calculations indicate that theoretically, our analysis is well-powered to identify variants with Beta values >6 in the MAF range examined (see Figure 5).


Environmental and genetic contributors to salivary testosterone levels in infants.

Xia K, Yu Y, Ahn M, Zhu H, Zou F, Gilmore JH, Knickmeyer RC - Front Endocrinol (Lausanne) (2014)

Correlation between effect sizes in full samples [correcting for log(10)transferrin] and subsamples with transferrin levels <0.50 mg/dl.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214198&req=5

Figure 4: Correlation between effect sizes in full samples [correcting for log(10)transferrin] and subsamples with transferrin levels <0.50 mg/dl.
Mentions: In males, no SNPs were significantly associated with salivary testosterone levels after adjusting for FDR in the full sample. The most significant association was for rs10923844, a variant of unknown function located downstream of HSD3B1 and HSD3B2 (adjusted p-value = 0.07, unadjusted p = 0.0002). This same SNP had an unadjusted p-value of 0.02 in the subsample of males with transferrin <0.50 mg/dl. Effect sizes for this variant were highly similar in the total male sample [adjusting for log(10)transferrin] and the subsample of males with transferrin <0.50 mg/dl (Beta = 6.26 and 6.02, respectively). Indeed, effect sizes for the full male sample are highly similar to the corresponding effect sizes in the subset of males with transferrin <0.50 mg/dl (see Figure 4). None of the previous GWAS hits for serum testosterone levels in adult males were significantly associated with salivary testosterone in infant males before or after adjusting for FDR in either the full sample or the subset of males with transferrin <0.50 mg/dl. In females, no SNPs were significantly associated with salivary testosterone levels after adjusting for FDR. The most significant associations were for two SNPs located upstream of ESR1 (rs3407085 and rs2295190) within the intron region of SYNE1 (spectrin repeat containing, nuclear envelope (1); adjusted and unadjusted p-values were 0.09 and 0.0004 for both variants (these variants are in complete linkage disequilibrium within our sample). Both variants had an unadjusted p-value of 0.04 in the subsample of females with transferrin <0.50 mg/dl. Effect sizes were highly similar for the total female sample [adjusting for log(10)transferrin] and the subsample of females with transferrin <0.50 mg/dl (Beta = −13.7 and −11.2, respectively), though we note that effect sizes for the full female sample do not correspond as well to the effect sizes in the reduced sample as compared to males (See Figure 4). Full results are available as supplemental data. Power calculations indicate that theoretically, our analysis is well-powered to identify variants with Beta values >6 in the MAF range examined (see Figure 5).

Bottom Line: The top hit in males was rs10923844, an SNP of unknown function located downstream of HSD3B1 and HSD3B2.The top hits in females were two SNPs located upstream of ESR1 (rs3407085 and rs2295190).RF analysis, which reflects joint and conditional effects of multiple variants, indicated that genes involved in regulation of reproductive function, particularly LHCGR, are related to salivary testosterone levels in male infants, as are genes involved in cholesterol production, transport, and removal, while genes involved in estrogen signaling are related to salivary testosterone levels in female infants.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of North Carolina at Chapel Hill , Chapel Hill, NC , USA.

ABSTRACT
Transient activation of the hypothalamic-pituitary-gonadal axis in early infancy plays an important role in male genital development and sexual differentiation of the brain, but factors contributing to individual variation in testosterone levels during this period are poorly understood. We measured salivary testosterone levels in 222 infants (119 males, 103 females, 108 singletons, 114 twins) between 2.70 and 4.80 months of age. We tested 16 major demographic and medical history variables for effects on inter-individual variation in salivary testosterone. Using the subset of twins, we estimated genetic and environmental contributions to salivary testosterone levels. Finally, we tested single nucleotide polymorphisms (SNPs) within ±5 kb of genes involved in testosterone synthesis, transport, signaling, and metabolism for associations with salivary testosterone using univariate tests and random forest (RF) analysis. We report an association between 5 min APGAR scores and salivary testosterone levels in males. Twin modeling indicated that individual variability in testosterone levels was primarily explained by environmental factors. Regarding genetic variation, univariate tests did not reveal any variants significantly associated with salivary testosterone after adjusting for false discovery rate. The top hit in males was rs10923844, an SNP of unknown function located downstream of HSD3B1 and HSD3B2. The top hits in females were two SNPs located upstream of ESR1 (rs3407085 and rs2295190). RF analysis, which reflects joint and conditional effects of multiple variants, indicated that genes involved in regulation of reproductive function, particularly LHCGR, are related to salivary testosterone levels in male infants, as are genes involved in cholesterol production, transport, and removal, while genes involved in estrogen signaling are related to salivary testosterone levels in female infants.

No MeSH data available.