PMC:4129400 / 38673-41424 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4129400","sourcedb":"PMC","sourceid":"4129400","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4129400","text":"We next examined the functional classifications, locations, and reproducibility of genetic loci affecting protein abundances. We compared the newly identified pQTL loci with eQTL loci that we identified using RNA-seq expression for the 373 genes with overlapping protein and mRNA measurements (Figure 4). We first compared the relative proportions of annotations of eQTLs and pQTLs versus all SNVs used in our study (Figure 4A; Table S11). eQTLs were significantly enriched near the 5′ and 3′ ends of genes and at the 5′ UTR (p = 6.63 × 10−9, p = 1.49 × 10−3, and p = 6.27 × 10−13, respectively) and depleted in introns (p = 1.42 × 10−3) (Figure 4B). This finding is consistent with observations from previous global eQTL studies that eQTLs tend to cluster near the TSSs of genes24,26 and in exons relative to introns.43 pQTLs were enriched near gene 3′ ends (1.14 × 10−3), in 5′ or 3′ UTRs (p = 0.03, p = 0.03), in synonymous coding variants (p = 0.02), and notably, in missense variants (p = 1.58 × 10−5) (Figure 4C). These observations indicated that genetic variants associated with protein level variation might involve protein stability or miRNA-mediated regulation of mRNA translational efficiency. We next examined the reproducibility of eQTLs across platforms and at the protein level (defined as a nominal p \u003c 0.05 with a concordant effect direction) as a function of the p value of the discovery association in RNA-seq. We observed that cis and trans eQTLs discovered at p \u003c 10−4 were more likely to replicate across platforms and as pQTLs than expected by chance (Figures 4D and 4E). All four of the most significant cis eQTLs (p \u003c 10−6) replicated by both the Illumina expression array and Affymetrix exon array, and three were nominally significant cis pQTLs. Two of these cis eQTLs were located in adjacent recombination blocks and associated with ZNF266; indeed, despite being split by an average 29 cM/Mb recombination rate across the 20 kb gene transcription region centered at chr19: 9,348,911,22 these SNPs remained in high LD (r2 = 0.99). However, trans eQTLs failed to replicate well across mRNA expression platforms or between mRNA and protein measurement platforms (Figure 4E). This observation was consistent with previously reported examples demonstrating the difficulty in replicating trans eQTLs.8,44 Only 1 of the 10 cis pQTLs (rs7256500 and ZNF266) and 6 of the 49 trans pQTLs identified at an FDR \u003c 0.20 replicated at the mRNA level, indicating that few genetic variants that were strongly associated with protein levels were also associated with mRNA expression (Figure S8). These observations suggested that many of these genetic variants might affect protein levels independently of their effect on transcript levels.","tracks":[{"project":"2_test","denotations":[{"id":"25087611-17873874-2046351","span":{"begin":782,"end":784},"obj":"17873874"},{"id":"25087611-20220758-2046351","span":{"begin":782,"end":784},"obj":"20220758"},{"id":"25087611-18846210-2046352","span":{"begin":818,"end":820},"obj":"18846210"},{"id":"25087611-17943122-2046353","span":{"begin":2013,"end":2015},"obj":"17943122"},{"id":"25087611-21637794-2046354","span":{"begin":2326,"end":2328},"obj":"21637794"},{"id":"25087611-20439777-2046354","span":{"begin":2326,"end":2328},"obj":"20439777"}],"attributes":[{"subj":"25087611-17873874-2046351","pred":"source","obj":"2_test"},{"subj":"25087611-20220758-2046351","pred":"source","obj":"2_test"},{"subj":"25087611-18846210-2046352","pred":"source","obj":"2_test"},{"subj":"25087611-17943122-2046353","pred":"source","obj":"2_test"},{"subj":"25087611-21637794-2046354","pred":"source","obj":"2_test"},{"subj":"25087611-20439777-2046354","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#9593ec","default":true}]}]}}