Genome-wide discovery for biomarkers using quantile regression at biobank scale

• Published in: Nature communications Vol. 15; no. 1; pp. 6460 - 13
• Main Authors: Wang, Chen, Wang, Tianying, Kiryluk, Krzysztof, Wei, Ying, Aschard, Hugues, Ionita-Laza, Iuliana
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31-07-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/114/2415; 631/208/205/2138; 692/53/2421; Basic Medicine; Biobanks; Biological Specimen Banks; Biomarkers; Computer Simulation; Genetic effects; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Genotype; Genotype & phenotype; Genotypes; Humanities and Social Sciences; Humans; Linear functions; Linear Models; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Models, Genetic; multidisciplinary; Phenotype; Phenotypes; Polymorphism, Single Nucleotide; Quantiles; Quantitative Trait Loci; Regression Analysis; Regression models; Risk groups; Science; Science (multidisciplinary); Subgroups; United Kingdom; United Kingdom; United Kingdom > UK
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50726-x

Genome-wide association studies (GWAS) for biomarkers important for clinical phenotypes can lead to clinically relevant discoveries. Conventional GWAS for quantitative traits are based on simplified regression models modeling the conditional mean of a phenotype as a linear function of genotype. We draw attention here to an alternative, lesser known approach, namely quantile regression that naturally extends linear regression to the analysis of the entire conditional distribution of a phenotype of interest. Quantile regression can be applied efficiently at biobank scale, while having some unique advantages such as (1) identifying variants with heterogeneous effects across quantiles of the phenotype distribution; (2) accommodating a wide range of phenotype distributions including non-normal distributions, with invariance of results to trait transformations; and (3) providing more detailed information about genotype-phenotype associations even for those associations identified by conventional GWAS. We show in simulations that quantile regression is powerful across both homogeneous and various heterogeneous models. Applications to 39 quantitative traits in the UK Biobank demonstrate that quantile regression can be a helpful complement to linear regression in GWAS and can identify variants with larger effects on high-risk subgroups of individuals but with lower or no contribution overall.
Here, the authors propose using quantile regression for genome-wide association studies with quantitative traits in UK Biobank, showing its advantages over linear regression in handling nonnormal distributions and identifying heterogeneous genetic effects.