Tissue-specific impact of FADS cluster variants on FADS1 and FADS2 gene expression

Abstract

Omega-6 (n-6) and omega-3 (n-3) long (≥ 20 carbon) chain polyunsaturated fatty acids (LC-PUFAs) play a critical role in human health and disease. Biosynthesis of LC-PUFAs from dietary 18 carbon PUFAs in tissues such as the liver is highly associated with genetic variation within the fatty acid desaturase (FADS) gene cluster, containing FADS1 and FADS2 that encode the rate-limiting desaturation enzymes in the LC-PUFA biosynthesis pathway. However, the molecular mechanisms by which FADS genetic variants affect LC-PUFA biosynthesis, and in which tissues, are unclear. The current study examined associations between common single nucleotide polymorphisms (SNPs) within the FADS gene cluster and FADS1 and FADS2 gene expression in 44 different human tissues (sample sizes ranging 70-361) from the Genotype-Tissue Expression (GTEx) Project. FADS1 and FADS2 expression were detected in all 44 tissues. Significant cis-eQTLs (within 1 megabase of each gene, False Discovery Rate, FDR<0.05, as defined by GTEx) were identified in 12 tissues for FADS1 gene expression and 23 tissues for FADS2 gene expression. Six tissues had significant (FDR< 0.05) eQTLs associated with both FADS1 and FADS2 (including artery, esophagus, heart, muscle, nerve, and thyroid). Interestingly, the identified eQTLs were consistently found to be associated in opposite directions for FADS1 and FADS2 expression. Taken together, findings from this study suggest common SNPs within the FADS gene cluster impact the transcription of FADS1 and FADS2 in numerous tissues and raise important questions about how the inverse expression of these two genes impact intermediate molecular (such a LC-PUFA and LC-PUFA-containing glycerolipid levels) and ultimately clinical phenotypes associated with inflammatory diseases and brain health.

Fig 1. FADS1 and FADS2 expression across 44 human tissues.

Boxplots of FADS1 (top) and FADS2 (bottom) mRNA expression (log₁₀RPKM—y axis) are shown across tissues (x-axis) from GTEx; outliers are shown as circles; median expression is represented as the center line.

Fig 2. FADS1 and FADS2 cis-eQTLs.

Significant eQTLS (FDR<0.05) associated with gene expression of FADS1 (A) or FADS2 (B) identified in 27 human tissues from GTEx. The significance of the detected association is represented as the size of the circle (larger the circle, more significant the result), and the color represents the direction of effect of the alternate (alt) allele (red for increased transcription with alt allele, blue for decreased transcription). FADS1 and FADS2 gene transcription start sites (TSS) and transcription end sites (TES) illustrate the location of FADS1 and FADS2 genes relative to the cis-eQTLs.

Fig 3. rs174548 genotype associations with FADS1 and FADS2 across tissues.

Nominal associations (effect size and 95% confidence interval) between rs174548 genotypes (G, alt allele vs C, ref allele) with FADS1 (A) and FADS2 (B) are shown across GTEx tissues. The effect size of the eQTLs was defined as the slope of the linear regression, comparing the alt allele (G) to the reference allele (C).

Fig 4. FADS1 and FADS2 expression by rs174548 genotype.

FADS1 (A) FADS2 (B) rank normalized gene expression (Y-axis) by rs174548 genotype (G: alt allele, C: ref allele) in the five tissues with significant (FDR<0.05) associations between rs174548 and FADS1 and FADS2 in the same tissues.