<i>FADS1</i> and <i>FADS2</i> expression across 44 human tissues.

<p>Boxplots of <i>FADS1</i> (top) and <i>FADS2</i> (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.</p

rs174548 genotype associations with <i>FADS1</i> and <i>FADS2</i> across tissues.

<p>Nominal associations (effect size and 95% confidence interval) between rs174548 genotypes (G, alt allele vs C, ref allele) with <i>FADS1</i> (A) and <i>FADS2</i> (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).</p

Tissue-specific impact of <i>FADS</i> cluster variants on <i>FADS1</i> and <i>FADS2</i> gene expression

<div><p>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 (<i>FADS)</i> gene cluster, containing <i>FADS1</i> and <i>FADS2</i> that encode the rate-limiting desaturation enzymes in the LC-PUFA biosynthesis pathway. However, the molecular mechanisms by which <i>FADS</i> 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 <i>FADS</i> gene cluster and <i>FADS1</i> and <i>FADS2</i> gene expression in 44 different human tissues (sample sizes ranging 70–361) from the Genotype-Tissue Expression (GTEx) Project. <i>FADS1</i> and <i>FADS2</i> 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 <i>FADS1</i> gene expression and 23 tissues for <i>FADS2</i> gene expression. Six tissues had significant (FDR< 0.05) eQTLs associated with both <i>FADS1</i> and <i>FADS2</i> (including artery, esophagus, heart, muscle, nerve, and thyroid). Interestingly, the identified eQTLs were consistently found to be associated in opposite directions for <i>FADS1</i> and <i>FADS2</i> expression. Taken together, findings from this study suggest common SNPs within the <i>FADS</i> gene cluster impact the transcription of <i>FADS1</i> and <i>FADS2</i> 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.</p></div

Targeted Deep Resequencing Identifies Coding Variants in the <i>PEAR1</i> Gene That Play a Role in Platelet Aggregation

<div><p>Platelet aggregation is heritable, and genome-wide association studies have detected strong associations with a common intronic variant of the platelet endothelial aggregation receptor1 (<i>PEAR1</i>) gene both in African American and European American individuals. In this study, we used a sequencing approach to identify additional exonic variants in <i>PEAR1</i> that may also determine variability in platelet aggregation in the GeneSTAR Study. A 0.3 Mb targeted region on chromosome 1q23.1 including the entire <i>PEAR1</i> gene was Sanger sequenced in 104 subjects (45% male, 49% African American, age = 52±13) selected on the basis of hyper- and hypo- aggregation across three different agonists (collagen, epinephrine, and adenosine diphosphate). Single-variant and multi-variant burden tests for association were performed. Of the 235 variants identified through sequencing, 61 were novel, and three of these were missense variants. More rare variants (MAF<5%) were noted in African Americans compared to European Americans (108 vs. 45). The common intronic GWAS-identified variant (rs12041331) demonstrated the most significant association signal in African Americans (p = 4.020×10⁻⁴); no association was seen for additional exonic variants in this group. In contrast, multi-variant burden tests indicated that exonic variants play a more significant role in European Americans (p = 0.0099 for the collective coding variants compared to p = 0.0565 for intronic variant rs12041331). Imputation of the individual exonic variants in the rest of the GeneSTAR European American cohort (N = 1,965) supports the results noted in the sequenced discovery sample: p = 3.56×10⁻⁴, 2.27×10⁻⁷, 5.20×10⁻⁵ for coding synonymous variant rs56260937 and collagen, epinephrine and adenosine diphosphate induced platelet aggregation, respectively. Sequencing approaches confirm that a common intronic variant has the strongest association with platelet aggregation in African Americans, and show that exonic variants play an additional role in platelet aggregation in European Americans.</p></div

<i>FADS1</i> and <i>FADS2</i> expression by rs174548 genotype.

<p><i>FADS1</i> (A) <i>FADS2</i> (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 <i>FADS1</i> and <i>FADS2</i> in the same tissues.</p

Adaptive Evolution of the <em>FADS</em> Gene Cluster within Africa

<div><p>Long chain polyunsaturated fatty acids (LC-PUFAs) are essential for brain structure, development, and function, and adequate dietary quantities of LC-PUFAs are thought to have been necessary for both brain expansion and the increase in brain complexity observed during modern human evolution. Previous studies conducted in largely European populations suggest that humans have limited capacity to synthesize brain LC-PUFAs such as docosahexaenoic acid (DHA) from plant-based medium chain (MC) PUFAs due to limited desaturase activity. Population-based differences in LC-PUFA levels and their product-to-substrate ratios can, in part, be explained by polymorphisms in the fatty acid desaturase (<em>FADS</em>) gene cluster, which have been associated with increased conversion of MC-PUFAs to LC-PUFAs. Here, we show evidence that these high efficiency converter alleles in the <em>FADS</em> gene cluster were likely driven to near fixation in African populations by positive selection ∼85 kya. We hypothesize that selection at <em>FADS</em> variants, which increase LC-PUFA synthesis from plant-based MC-PUFAs, played an important role in allowing African populations obligatorily tethered to marine sources for LC-PUFAs in isolated geographic regions, to rapidly expand throughout the African continent 60–80 kya.</p> </div

Median-joining network for the relationship of haplotypes of 1,092 individuals in a ∼30

<p> <b>kb block of LD including </b><b><i>FADS1</i></b><b>.</b> Circles represent haplotypes with an area proportional to frequency. Singleton haplotypes were not shown. “Ancestral” is a reconstructed haplotype carrying the ancestral (chimpanzee) allele at each position as illustrated in black.</p

XP-EHH scores across the 300kb region (chr11∶61467097–61759006, hg19) around the <i>FADS</i> gene cluster in populations from Africa (blue) and Europe (red) within the HGDP.

<p>SNP rs174737 is illustrated with the black dot on the African curve. The teal shaded box represents the ∼30 kb haplotype block noted within the African samples and the three black bars represent <i>FADS1, FADS2</i> and <i>FADS3</i> from left to right, respectively along with direction of transcription. Dotted line represents the threshold for an empirical P = 0.01 comparing across all windows in the genome for XP-EHH.</p

Geographic distribution of <i>derived</i> allele frequencies in a 100

<p> <b>kb region surrounding rs174537 in the 52 populations represented in the Human Genome Diversity Panel Data. </b><b>Panel A</b> represents physical position of the SNPs relative to genes in the region, <b>Panel B</b> is SNP name (derived allele), <b>Panel C</b> is frequency of derived allele (in orange) in the populations clustered based on geography, <b>Panel D</b> is an indication of the allele associated with increased LC-PUFA metabolism in published association studies, and Panel E is the detailed overview of rs174537 showing is near fixation within Africa.</p

Summary of sliding window analysis across a 300 kb region (chr11∶61467097–61759006, hg19) centered on the <i>FADS</i> gene cluster for two African (YRI and LWK) versus eight non-African populations (IBS, CEU, GBR, FIN, TSI, JPT, CHB and CHS).

<p>Genetic diversity π, Tajima’s D, Fay & Wu’s H, and pairwise F_ST were calculated using a window size of 5 kb and an overlap of 1 kb. The teal shaded box represents the ∼30 kb haplotype block noted within the African samples and the three black bars represent <i>FADS1, FADS2</i> and <i>FADS3</i> from left to right, respectively along with direction of transcription. Dotted lines represent the threshold for an empirical P = 0.01 comparing across all windows in the genome for Tajima’s D, Fay & Wu’s H.</p