Research ArticleHUMAN GENETICS

GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

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Science Advances  04 Sep 2019:
Vol. 5, no. 9, eaaw3095
DOI: 10.1126/sciadv.aaw3095
  • Fig. 1 Regional association and forest plot of the novel genome-wide significant locus associated with BMI-AP.

    Purple diamond indicates the most significantly associated SNP in stage 1 meta-analysis, and circles represent the other SNPs in the region, with coloring from blue to red corresponding to r2 values from 0 to 1 with the index SNP. The SNP position refers to the National Center for Biotechnology Information (NCBI) build 36. Estimated recombination rates are from HapMap build 36. Forest plots from the meta-analysis for each of the identified loci are plotted abreast. Effect size [95% confidence interval (CI)] in each individual study, discovery, follow-up, and combined meta-analysis stages is presented from fixed-effects models (heterogeneity of the SNP rs9436303 in LEPR/LEPROT; see fig. S6). At this locus, there was heterogeneity between the studies in discovery (I2 = 72.1%, P = 0.01) and combined stage (I2 = 59.3%, P = 0.002) fixed-effects meta-analyses that was mainly due to LISA-D, EDEN, and the larger well-defined NFBC1966 study (fig. S6, A and D). Removing the studies that showed inflated results from meta-analyses did not change the point estimates (fig. S6, C, F, and G). Both fixed- and random-effects models gave very similar results (fig. S6, B and E).

  • Fig. 2 Tissue-specific posterior probabilities (PPs) of colocalization for LEPR and LEPROT.

    PP of eQTL and GWAS SNP sharing a causal variant regulating the gene expression levels of (A) LEPR and (B) LEPROT. Colocalization reported for GTEX eQTLs data in 34 tissues that express at least one of the genes. Bar plot color-coded according to the –log10 P value eQTL direct lookup in the corresponding GTEx tissue of the GWAS SNP. LEPR and LEPROT eQTLs colocalized with BMI-AP variant rs9436303.

  • Fig. 3 Genetic correlations between five early growth traits and a subset of 37 phenotypes.

    Only a selected list of 37 phenotypes is represented on the correlation matrix. Genetic correlation results for all 72 phenotypes are given in table S16. Blue, positive genetic correlation; red, negative genetic correlation. The correlation matrix underneath represents the genetic correlation among the five early growth traits themselves. The size of the colored squares is proportional to the P value, where larger squares represent a smaller P value. Genetic correlations that are different from 0 at P < 0.05 are marked with an asterisk. The genetic correlations that are different from 0 at an FDR of 1% are marked with a circle. Genetic correlations estimated with stage 1 meta-analysis GWAS summary statistics from the current and literature studies using LD score regression.

  • Fig. 4 Adult BMI GRS analysis of early growth traits.

    Scatter plots show the effect size estimates (SD units) of the 97 adult BMI-associated SNP in GIANT consortium in the x axis and the corresponding effect size estimates (SD units) of the looked-up SNP of stage 1 meta-analysis GWAS on (A) BMI-AR and (B) Age-AR in the y axis. The effect size of the adult BMI increasing allele is plotted. The solid red line is the estimated effect of the GRS on the early growth phenotype, taking into account the uncertainty of the point estimates. The dashed line is the 95% CI of the predicted effect. Stage 1 meta-analysis GWAS SNPs with P < 0.05 are plotted with a solid circle and labeled with the nearest gene name. The scatter plots of the other early growth phenotypes are given in fig. S10.

  • Fig. 5 Proposed model of child BMI suggesting the superimposition of two biological phenomena under the genetic control of different loci.

    The schematic diagram shows the four genome-wide significant loci associated with early childhood growth traits and highlights the fact that only SNPs associated with phenotypes ascertained at AR are associated with adult BMI. The red curve represents the mean BMI trajectory from birth to puberty in the NFBC1966 cohort.

  • Table 1 Summary statistics of the eight independent SNPs associated with PWV in infancy, BMI-AP in infancy, Age-AR, and BMI-AR in discovery (stage 1) and follow-up (stage 2) and in combined meta-analyses.

    Stage 1 (n = 7,215)Stage 2 (n = 16,550)Combined (n = 22,769)
    Index SNPChromosome
    position*
    In/near
    gene
    Effect allele/
    other allele
    Effect allele
    frequency
    Effect
    size (SE)
    PEffect size
    (SE)
    PEffect
    size (SE)
    P
    PWV (kg/month)
    rs2860323chr2:614210TMEM18G/A0.120.09 (0.02)5.9 × 10−50.02 (0.02)4.7 × 10−10.06 (0.02)3.9 × 10−4
    BMI-AP (kg/m2)
    rs9436303chr1:65430991LEPR/LEPROTG/A0.220.13 (0.02)4.7 × 10−80.05 (0.01)6.7 × 10−40.07 (0.01)8.3 × 10−9
    rs10515235chr5:96323352PCSK1A/G0.210.09 (0.02)9.7 × 10−70.03 (0.01)1.5 × 10−20.05 (0.01)2.4 × 10−6
    Age-AR (years)
    rs1421085chr16:53767042FTOC/T0.25−0.10 (0.02)6.1 × 10−8−0.13 (0.01)7.1 × 10−24−0.12 (0.01)3.1 × 10−30
    rs2956578chr5:36497552Intergenic
    region
    G/A0.310.11 (0.02)6.7 × 10−80.00 (0.01)8.3 × 10−10.04 (0.01)1.1 × 10−3
    rs2817419chr6:50845193TFAP2BA/G0.76−0.10 (0.02)2.9 × 10−6−0.07 (0.01)1.8 × 10−6−0.08 (0.01)4.4 × 10−11
    BMI-AR (kg/m2)
    rs10938397chr4:45180510GNPDA2G/A0.350.09 (0.02)5.4 × 10−60.05 (0.01)3.1 × 10−40.06 (0.01)2.9 × 10−8
    rs2055816chr11:85406487DLG2C/T0.25−0.13 (0.02)1.4 × 10−7−0.03 (0.02)1.8 × 10−1−0.07 (0.02)5.1 × 10−6

    *SNP positions are according to dbSNP build 147.

    †The effect size is the change in SDs per effect allele from linear regression, adjusted for child’s sex and principal components (PCs) assuming an additive genetic model. BMI-AP was additionally adjusted for gestational age (GA). PWV, BMI-AP, and BMI-AR were log-transformed because of skewness in their distribution. Original phenotype measurement units are denoted in parentheses. None of the loci for PHV passed the selection criteria for stage 2 follow-up. P values for discovery and combined analysis are shown in bold if genome-wide significant (P < 5 × 10−8). The maximum sample size used in meta-analyses of each stage is shown in parentheses. Results are from inverse-variance fixed-effects meta-analysis of European ancestry children. The effect allele for each SNP is labeled on the positive strand according to HapMap.

    ‡Intergenic region between RANBP3L and SLC1A3.

    • Table 2 GWAS loci colocalized with eQTL in postmortem tissues from the GTEx data.

      Colocalization results refer to GWAS and eQTL SNP. PP, posterior probability

      ChrNearest geneTraitGWAS SNPGWAS SNP
      P value
      TissueeQTL SNPeQTL
      P value
      eQTL geneTop eQTL
      SNP*(R2)
      Colocalization
      PP (%)**
      1LEPR/LEPROTBMI-APrs94363038.3 × 10−9Thyroidrs94363017.9 × 10−7LEPROTrs9436745 (0.78)99
      Esophagus
      muscularis
      rs18872851.6 × 10−6LEPROTrs9436745 (0.78)98
      Cell EBV-
      transformed
      lymphocytes
      rs18872851.2 × 10−7LEPRrs77848204 (0.22)96
      6TFAP2BAge-ARrs28174194.4 × 10−11Testisrs26357272.9 × 10−7TFAP2Brs2635727 (0.91)99
      Sun-exposed
      skin lower leg
      rs26357274.2 × 10−6TFAP2Brs2635727 (0.91)98

      *R2 values between GWAS SNP and GTEx top eQTL SNP for each gene (eGene) are shown for reference. Only results with a ** posterior probability (PP) of a shared causal variant of >95% are reported.

      • Table 3 SNP heritability of the early growth traits.

        SNP heritability estimated with LD score using all common SNPs (MAF > 0.01) in stage 1 GWAS meta-analysis.

        TraitEstimated
        heritability
        SE95% CIMean χ2P
        BMI-AP0.290.080.130.461.034.7 × 10−4
        BMI-AR0.380.080.220.531.0132.7 × 10−6
        Age-AP−0.030.08−0.180.131.0017.4 × 10−1
        Age-AR0.360.080.200.521.0071.1 × 10−5
        PHV0.110.07−0.030.251.0061.3 × 10−1
        PWV0.320.070.180.451.0112.5 × 10−6

      Supplementary Materials

      • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/5/9/eaaw3095/DC1

        Table S1. Study characteristics, exclusions, genotyping, quality control, and imputation of stage 1 studies.

        Table S2. Study characteristics, exclusions, genotyping, and quality control in stage 2 studies.

        Table S3. The SNP selection criteria used for selecting loci from stage 1 GWAS meta-analysis data and proxies used for follow-up in stage 2.

        Table S4. The association of the four genome-wide significant SNPs or proxies in high LD (R2 > 0.8) with other phenotypes in published GWASs retrieved from PhenoScanner database.

        Table S5. The association of the four genome-wide significant SNPs with other phenotypes in the Gene Atlas PheWAS on the UK Biobank data.

        Table S6. Conditional analysis in the NFBC1966 data (N = 2585) of the BMI-AP association with the lead GWAS SNP rs9436303 adjusting for the early-onset obesity SNP rs11208659.

        Table S7. Variant effect prediction of the four genome-wide significant SNPs.

        Table S8. Biological and functional mechanisms of the nearest genes to the four genome-wide significant SNPs.

        Table S9. Top eQTLs (FDR < 1%) in five ex vivo tissues in high LD (R2 > 0.8) with the lead GWAS SNPs in LEPR/LEPROT locus.

        Table S10. Direct lookup on eQTL (P < 0.001) data in five ex vivo tissues of the lead GWAS SNPs in LEPR/LEPROT locus.

        Table S11. Direct lookup of the lead GWAS SNPs in LEPR/LEPROT and TFAP2B locus on methylation QTL (FDR < 1%) in blood drawn at five different life stages: mother’s pregnancy (~29.2 years, SD = 4.4 years) and middle age (~47.5 years, SD = 4.5 years), and offspring’s birth (0 years), childhood (~7.5 years, SD = 0.15 years), and adolescence (~17.1 years, SD = 1.0 years).

        Table S12. Cross-trait genetic correlations between five early growth traits and 80 other GWAS phenotypes from LD score regression analyses.

        Table S13. The directional consistency between phenotypic and genetic correlations for the same trait.

        Table S14. Lookup of the GIANT consortium BMI-associated SNPs on the stage 1 GWAS meta-analyses of the six early growth traits.

        Table S15. The GRS of adult BMI using SNP weights from the GIANT consortium applied to the early growth trait summary statistics from the stage 1 GWAS meta-analyses.

        Table S16. Gene set enrichment analysis (MAGENTA) of biological pathways based on the discovery GWAS.

        Table S17. Detailed description of IGF-1 signaling pathway associated with AGE-AR (FDR < 0.05) in MAGENTA gene set enrichment analysis.

        Table S18. SNP heritability of the early growth traits estimated with SumHer and LD score.

        Table S19. Individual contributions of authors.

        Fig. S1. Graphical illustration of height and weight growth patterns and the derived measures of early growth traits used in the present study.

        Fig. S2. Summary of study design.

        Fig. S3. The participating studies with their geographical location.

        Fig. S4. The Manhattan plot and quantile-quantile plot of the association P values for the six early growth phenotypes from stage 1 genome-wide association analyses.

        Fig. S5. Regional association and forest plots of the three genome-wide significant loci associated with early growth traits that have been previously linked with adult BMI.

        Fig. S6. Heterogeneity analyses of the GWAS lead SNP rs9436303 at LEPR/LEPROT locus.

        Fig. S7. Regional plots of the GWAS and GTEx cis-eQTL data used in the colocalization analysis of the early growth–associated loci.

        Fig. S8. Tissue-specific PPs of colocalization of TFAP2B.

        Fig. S9. Genomic annotation analysis of the colocalized variants involved in the regulation of LEPR, LEPROT, and TFAP2B gene expression.

        Fig. S10. Adult BMI GRS analysis of early growth traits.

        Note S1. Literature search for epidemiological associations between early growth traits and childhood and adult traits.

        Note S2. Cohort description (see also tables S1 and S2 for genotyping details and figs. S1 to S3).

        Note S3. Funding and acknowledgments by the study.

        References (61104)

      • Supplementary Materials

        The PDF file includes:

        • Legends for tables S1 and S2
        • Table S3. The SNP selection criteria used for selecting loci from stage 1 GWAS meta-analysis data and proxies used for follow-up in stage 2.
        • Legends for tables S4 and S5
        • Table S6. Conditional analysis in the NFBC1966 data (N = 2585) of the BMI-AP association with the lead GWAS SNP rs9436303 adjusting for the early-onset obesity SNP rs11208659.
        • Legend for table S7
        • Table S8. Biological and functional mechanisms of the nearest genes to the four genome-wide significant SNPs.
        • Table S9. Top eQTLs (FDR < 1%) in five ex vivo tissues in high LD (R2 > 0.8) with the lead GWAS SNPs in LEPR/LEPROT locus.
        • Table S10. Direct lookup on eQTL (P < 0.001) data in five ex vivo tissues of the lead GWAS SNPs in LEPR/LEPROT locus.
        • Legends for tables S11 and S12
        • Table S13. The directional consistency between phenotypic and genetic correlations for the same trait.
        • Legends for tables S14 and S15
        • Table S16. Gene set enrichment analysis (MAGENTA) of biological pathways based on the discovery GWAS.
        • Table S17. Detailed description of IGF-1 signaling pathway associated with AGE-AR (FDR < 0.05) in MAGENTA gene set enrichment analysis.
        • Legends for tables S18 and S19
        • Fig. S1. Graphical illustration of height and weight growth patterns and the derived measures of early growth traits used in the present study.
        • Fig. S2. Summary of study design.
        • Fig. S3. The participating studies with their geographical location.
        • Fig. S4. The Manhattan plot and quantile-quantile plot of the association P values for the six early growth phenotypes from stage 1 genome-wide association analyses.
        • Fig. S5. Regional association and forest plots of the three genome-wide significant loci associated with early growth traits that have been previously linked with adult BMI.
        • Fig. S6. Heterogeneity analyses of the GWAS lead SNP rs9436303 at LEPR/LEPROT locus.
        • Fig. S7. Regional plots of the GWAS and GTEx cis-eQTL data used in the colocalization analysis of the early growth–associated loci.
        • Fig. S8. Tissue-specific PPs of colocalization of TFAP2B.
        • Fig. S9. Genomic annotation analysis of the colocalized variants involved in the regulation of LEPR, LEPROT, and TFAP2B gene expression.
        • Fig. S10. Adult BMI GRS analysis of early growth traits.
        • Note S1. Literature search for epidemiological associations between early growth traits and childhood and adult traits.
        • Note S2. Cohort description (see also tables S1 and S2 for genotyping details and figs. S1 to S3).
        • Note S3. Funding and acknowledgments by the study.
        • References (61104)

        Download PDF

        Other Supplementary Material for this manuscript includes the following:

        • Table S1 (Microsoft Excel format). Study characteristics, exclusions, genotyping, quality control, and imputation of stage 1 studies.
        • Table S2 (Microsoft Excel format). Study characteristics, exclusions, genotyping, and quality control in stage 2 studies.
        • Table S4 (Microsoft Excel format). The association of the four genome-wide significant SNPs or proxies in high LD (R2 > 0.8) with other phenotypes in published GWASs retrieved from PhenoScanner database.
        • Table S5 (Microsoft Excel format). The association of the four genome-wide significant SNPs with other phenotypes in the Gene Atlas PheWAS on the UK Biobank data.
        • Table S7 (Microsoft Excel format). Variant effect prediction of the four genome-wide significant SNPs.
        • Table S11 (Microsoft Excel format). Direct lookup of the lead GWAS SNPs in LEPR/LEPROT and TFAP2B locus on methylation QTL (FDR < 1%) in blood drawn at five different life stages: mother’s pregnancy (~29.2 years, SD = 4.4 years) and middle age (~47.5 years, SD = 4.5 years), and offspring’s birth (0 years), childhood (~7.5 years, SD = 0.15 years), and adolescence (~17.1 years, SD = 1.0 years).
        • Table S12 (Microsoft Excel format). Cross-trait genetic correlations between five early growth traits and 80 other GWAS phenotypes from LD score regression analyses.
        • Table S14 (Microsoft Excel format). Lookup of the GIANT consortium BMI-associated SNPs on the stage 1 GWAS meta-analyses of the six early growth traits.
        • Table S15 (Microsoft Excel format). The GRS of adult BMI using SNP weights from the GIANT consortium applied to the early growth trait summary statistics from the stage 1 GWAS meta-analyses.
        • Table S18 (Microsoft Excel format). SNP heritability of the early growth traits estimated with SumHer and LD score.
        • Table S19 (Microsoft Excel format). Individual contributions of authors.

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