Strikingly, we find clear enrichment of shared directional signal for most SNPs, even for SNPs with p values as large as 0.5 (
Figure 1C). Across all SNPs genome-wide, the median SNP is associated with an effect size of 0.14 mm, which is approximately one-tenth the median effect size of genome-wide significant SNPs (1.43 mm). We also obtained similar results starting from a smaller family-based GWAS, confirming that the signals are not driven by confounding from population structure (
Supplemental Information). Putting the various lines of evidence together, we estimate that more than 100,000 SNPs exert independent causal effects on height, similar to an early estimate of 93,000 causal variants based on a different approach (
Supplemental Information).
In summary, we conclude that there is an extremely large number of causal variants with tiny effect sizes on height and, moreover, that these are spread very widely across the genome, such that most 100-kb windows contribute to variance in height. More generally, the heritability of complex traits and diseases is spread broadly across the genome (Loh et al., 2015, Shi et al., 2016), implying that a substantial fraction of all genes contribute to variation in disease risk. These observations seem inconsistent with the expectation that complex trait variants are primarily in specific biologically relevant genes and pathways. To explore this further, we turn next to data on functional enrichment of signals.