Genome-wide association studies (GWAS) have successfully identified thousands of genomic loci that are associated with complex human traits and disease. Many GWAS loci are found in non-coding regions of the genome, making functional interpretation difficult. These variants, however, are likely to contribute to human traits through effects on gene regulation. Chromatin accessibility is a hallmark of gene regulatory elements, as it determines the ability of transcription factors and other regulatory proteins to access DNA and influence gene expression. To elucidate and characterize the regulatory mechanisms underlying GWAS signals, I investigated the causal contribution of genetic variants that have functional effects on chromatin accessibility. Through experiments performed across thousands of publicly available samples, as well as in nearly 200 human liver samples that I generated in-house, I identified tens of thousands of common genetic variants associated with chromatin accessibility effects. Considering diverse tissue and cell types from hundreds of projects, I linked thousands of lead signals at GWAS loci to tagged variants with effects on chromatin accessibility and gene expression for a collection of diverse complex human traits. In a well-powered study that aimed to characterize chromatin accessibility effects in the liver, I identified hundreds of GWAS signals for blood lipids traits where genetic effects on chromatin accessibility are likely causal. I combined these data with other public resources of gene regulatory variation to perform a comprehensive mechanistic characterization of known blood lipids GWAS signals. I generated a mechanistic hypothesis for over 75% of the current known blood lipids GWAS variants from a study performed in individuals of diverse ancestral backgrounds. While a substantial advance, these experiments illustrated that additional experimental work will be necessary to elucidate a potential mechanism for all association signals identified across the spectrum of human complex traits.