A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Abstract

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

Polygene Varianten und Epigenetik bei Adipositas

“…Sechs neue Loci wurden für diesen Composite-Phänotyp identifiziert. Die Autoren [39] betonen den Wert der Verwendung von multiplen Merkmalen zur Definition komplexer Phänotypen, da diese dabei helfen, Varianten zu erkennen, die nicht durch Einzelphänotypanalysen identifiziert wurden. Sie könnten Aufschluss über neue biologische Signalwege geben.…”

“…Interessanterweise war das BMI-erhöhende Allel des MC4R-Locus auch mit einer gesteigerten Körperhöhe assoziiert (siehe auch [35]), während das BMI-erhöhende Allel am POMC/ADCY3-Locus mit einer verminderten Körpergröße assoziiert war. Einige Loci könnten folglich mit einem komplexeren Körperformphänotyp assoziiert sein, der nicht von der aktuellen GWAS zu einzelnen Phänotypen erfasst wird [39].…”

Genetic differences between extreme and composite constitution types from whole exome sequences reveal actionable variations

“…Thus even if the cohort size in PheWAS might be in millions with significant GWAS associations, the subsequent genotype-phenotype associations of the variants are in relatively smaller sample sizes. It is being felt that extending the GWAS to systems' level with deeper phenotypes and composite traits can accelerate predictive marker discoveries [6,19]. Exome sequencing of extreme phenotypes in smaller sample sizes (i.e.…”

Using composite phenotypes to reveal hidden physiological heterogeneity and model oxygen saturation variation of high altitude acclimatization in a Chinese Han longitudinal cohort

“…combinations of physiological phenotypes could become a promising alternative 13–15 . There are several methods to extract composite phenotypes from multiple traits, such as Principal Component Analysis (PCA)-based methods 14,16,17 and Partial Least Squares (PLS)-based methods 9,18,19 . PLS-based methods have better performance than PCA-based methods 18,19 .…”