Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

Abstract

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.

Keywords: DXA traits; UK Biobank; UK10K; anthropometry; genetic association study; imputation; next-generation whole-genome sequencing.

Figure 1

Heatmap of Pairwise Genetic Correlation Estimates between Anthropometric Traits Correlation estimates with their 95% confidence intervals and 5% FDR q values across all 66 possible pairs are given in Table S6. Abbreviations are as follows: BMI, body mass index; WHR, waist to hip ratio; WaistBMIadj, waist circumference adjusted for BMI; HipBMIadj, hip circumference adjusted for BMI; WHRBMIadj, waist to hip ratio adjusted for BMI; TFM, total fat mass; TLM, total lean mass; TRFM, trunk fat mass.

Figure 2

Enrichment of Discovery Meta-analysis Results in Mendelian Height-, Monogenic Obesity-, Syndromic Obesity-, and Mendelian Lipodystrophy-Associated Genes We used independent variants (r² < 0.2) with MAF ≥ 0.1% (left) and after excluding previously reported loci (±500 kb) (right). Shown are Mendelian height (A and B), monogenic obesity (C and D), syndromic obesity (E and F), and Mendelian lipodystrophy (G and H). Enrichment of signal is observed if the p value (one-sided) from the binomial test of the observed versus the expected number of variants with p ≤ 10⁻⁵ in Mendelian-associated genes (as calculated by GREAT and denoted by the red dot) is less than 0.05/4.482 (5% significance level Bonferroni corrected for the effective number of independent traits; horizontal red line). Observed and expected counts, Bonferroni corrected p values, and FDR q values are given in Table S24. Abbreviations are as follows: BMI, body mass index; WHR, waist to hip ratio; WaistBMIadj, waist circumference adjusted for BMI; HipBMIadj, hip circumference adjusted for BMI; WHRBMIadj, waist to hip ratio adjusted for BMI; TFM, total fat mass; TLM, total lean mass; TRFM, trunk fat mass.

Figure 3

Combined Information from Fine-Mapping Methods, Functional Prediction Scores, and eQTL Analysis to Assess the Overall Evidence Supporting Functional and Causal Interpretation at Fine-Mapped Regions of Newly Identified Variants Example of fine-mapping and annotation at the ADAMTS17 (left) and SSC5D (right) loci for association with height. LocusZoom regional association plot shown in (A) and posterior probability (PP) statistics shown in (B) are from the fine-mapping methods CAVIARBF and PRFScore (only variants with PP > 0.1 in either methods are shown); genome-wide annotation of variants (GWAVA) scores; genomic evolutionary rate profiling (GERP) scores; average GERP (in a 100 bp window around each variant) scores; whether the variant is an eQTL signal; number of cell lines in which the variant overlaps with a DNase footprints (peak calls from ENCODE); number of overlapping transcriptional factor binding sites based on ENCODE and JASPAR ChIP-seq; number of cell lines in which the queried locus overlaps with a DNase hypersensitivity site (ENCODE data, peaks from Ensembl); and Variant Effect Predictor (VEP) genic annotation. Circle sizes and colors for all scores are scaled with respect to score type and numbers are plotted below each circle. Probabilities of causality from CAVIARBF and PRFScore are colored in shades of purple. GWAVA scores range between [0,1] and scores greater than 0.5 indicate functionality (colored in white for scores < 0.5 and in shades of orchid for scores > 0.5). GERP scores range between [−12.3,6.17] with scores above zero indicating constraint (colored in white for scores < 0 and in shades of orchid for scores > 0).

Figure 4

Power to Detect Association in the Discovery Stage, Stage 1 Effect sizes and 95% confidence intervals (absolute value of beta, expressed in standard deviation units) as a function of minor allele frequencies (MAF), based on stage 1 of this study. Newly reported variants are denoted in diamonds, and previously reported variants that reach genome-wide significance (p ≤ 5 × 10⁻⁸, two-sided) in the discovery stage are denoted in circles. The curves indicate 80% power at the genome-wide significance threshold of p ≤ 5 × 10⁻⁸, for five representative sample sizes of the discovery stage: (1) height, BMI, weight; (2) TFM, TLM; (3) TRFM; (4) waist circumference, waist circumference adjusted for BMI; (5) hip circumference, waist to hip ratio, hip circumference adjusted for BMI, waist to hip ratio adjusted for BMI. The sample size for height (blue line) had 80% power to detect associations down to 0.1% MAF for betas ≥ 0.19 standard deviations (0.36 and 0.23 for TFM [orange] and waist to hip ratio [purple], respectively; not plotted). Further power calculations for different sample sizes are given in Figure S32. Abbreviations are as follows: BMI, body mass index; WHR, waist to hip ratio; WaistBMIadj, waist circumference adjusted for BMI; HipBMIadj, hip circumference adjusted for BMI; WHRBMIadj, waist to hip ratio adjusted for BMI; TFM, total fat mass; TLM, total lean mass; TRFM, trunk fat mass.