Research

Research Interest

Most traits in humans and other organisms, including many diseases, are complex. This means that phenotypic differences between individuals arise from the cumulative effects of many genetic loci, each contributing a small effect. My work focuses on developing statistical and computational methods to understand how genetic variation contributes to complex traits and how it differs among populations.

My areas of interest include:

Functional Genomics: gene expression regulation and its impact on complex traits
Evolution of Complex Traits: polygenic adaptation and demographic history

Beyond these areas, I have a broad interest in statistical genetics and population genetics.

Functional Genomics

Most genetic effects on complex traits are mediated through the regulation of gene expression. However, eQTLs identified from bulk RNA studies explain only ~20% of GWAS signals. Recently, large-scale single-cell RNA-seq (scRNA-seq) data have enabled the identification of eQTLs at cell type resolution, which has succeeded in explaining additional GWAS signals. Nonetheless, most GWAS hits remain unexplained, and the global nature of gene expression regulation is still unclear. To tackle these challenges, we utilize single-cell multi-omics data (e.g., scRNA-seq and scATAC-seq) and develop statistical methods to uncover the underlying mechanisms of gene regulation and their contributions to complex traits. We specifically investigated cell type-specific and trans regulation and their impact on complex traits. Preliminary results are detailed in Chen & Dahl 2024, with more advanced findings to be published soon (Chen, ..., Dahl, In prep).

Figure 4 in Chen & Dahl 2024 Nat Commun

Chen M, Dahl A. A robust model for cell type-specific interindividual variation in single-cell RNA sequencing data. (2024) Nat Commun.

Chen M, ..., Dahl A. Unbiasedly partitioning the heritability of scRNA-seq data reveals that the vast majority of cell type-specific gene regulation lies in trans. In prep.

Evolution of Complex Traits

Complex traits typically evolve through polygenic adaptation, a process where coordinated shifts in allele frequencies across multiple loci enable rapid trait evolution. However, detecting polygenic adaptation is challenging due to the confounding effects from subtle forms of population structure arising from recent demographic history. To address this, we developed novel strategies to infer polygenic adaptation while controlling for complex demographic backgrounds.

Chen M, Sidore C, Akiyama M, Ishigaki K, Kamatani Y, Schlessinger D, Cucca F, Okada Y, Chiang C. Evidence of Polygenic Adaptation in Sardinia at Height-Associated Loci Ascertained from the Biobank. (2020) AJHG

Chen M, Chiang C. Allele Frequency Differentiation at Height-associated SNPs among Continental Human Populations. (2021) EJHG

Figure 5 in Chen, ..., Chiang 2020 AJHG

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