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Idiopathic achalasia (IA) is a severe motility disorder characterized by neuronal degeneration in the myenteric plexus, but the etiology remains largely unknown. We performed whole-exome sequencing (WES) in 100 IA-affected individuals and 313 non-IA control subjects and validated the results in 230 IA-affected individuals and 1,760 non-IA control subjects. Common missense variants rs1705003 (CUTA, GenBank: NC_000006.11:g.33385953A>G) and rs1126511 (HLA-DPB1, GenBank: NC_000006.11:g.33048466G>T) at 6p21.32 were reproducibly associated with increased risk of IA (rs1126511: OR = 1.83, p = 2.34 × 10 -9 ; rs1705003: OR = 2.37, p = 3.21 × 10 -7 ), meeting exome-wide significance. Both variants can affect the expression of their target genes at the transcript level. An array-based association analysis in 280 affected individuals and 1,121 control subjects determined the same signal at 6p21.32. Further conditional analyses supported that the two missense variants identified in WES-based association study were potential causal variants of IA. For rare variants, the top genes identified by gene-based analysis were significantly enriched in nerve and muscle phenotypic genes in the mouse. Moreover, the functional rare variants in these genes tended to cooccur in IA-affected individuals. In an independent cohort, we successfully validated three rare variants (CREB5, GenBank: NC_000007.13:g.28848865G>T; ESYT3, GenBank: NC_000003.11:g.138183253C>T; and LPIN1, GenBank: NC_000002.11:g.11925128A>G) which heightens the risk of developing IA. Our study identified and validated two common variants and three rare variants associated with IA in immunologic and neurological genes, providing new insight into the etiology of IA., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Cancer susceptibility loci identified in reported genome-wide association studies (GWAS) are often tumor-specific; however, evidence of pleiotropy of some genes/loci has also been observed and biologically plausible. We hypothesized that there are important regions in the genome harboring genetic variants associated with risk of multiple types of cancer. In the current study, we attempted to map genetic variants that have consistent effects on risk of multiple cancers using our existing genome-wide scan data of lung cancer, noncardia gastric cancer, and esophageal squamous-cell carcinoma with overall 5,368 cases and 4,006 controls (GWAS stage), followed by a further evaluation in additional 9,001 cases with one of these cancer types and 11,436 controls (replication stage). Five variants satisfying the criteria of pleiotropy with p values from 1.10 × 10(-8) to 8.96 × 10(-6) for genome-wide scans of three cancer types were further evaluated in the replication stage. We found consistent associations of rs2494938 at 6p21.1 and rs2285947 at 7p15.3 with these three cancers in both GWAS and replication stages. In combined samples of GWAS and replication stages, the minor alleles of rs2494938 and rs2285947 were significantly associated with an increased risk of the cancers (odds ratio [OR] = 1.15, 95% confidence interval [CI], 1.10-1.19 and OR = 1.17, 95% CI, 1.12-1.21), with the p values being 1.20 × 10(-12) and 1.26 × 10(-16), respectively, which are at a genome-wide significance level. Our findings highlight the potential importance of variants at 6p21.1 and 7p15.3 in the susceptibility to multiple cancers., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Splicing quantitative trait loci (sQTLs) have been demonstrated to contribute to disease etiology by affecting alternative splicing. However, the role of sQTLs in the development of non-small-cell lung cancer (NSCLC) remains unknown. Thus, we performed a genome-wide sQTL study to identify genetic variants that affect alternative splicing in lung tissues from 116 individuals of Chinese ancestry, which resulted in the identification of 1,385 sQTL-harboring genes (sGenes) containing 378,210 significant variant-intron pairs. A comprehensive characterization of these sQTLs showed that they were enriched in actively transcribed regions, genetic regulatory elements, and splicing-factor-binding sites. Moreover, sQTLs were largely distinct from expression quantitative trait loci (eQTLs) and showed significant enrichment in potential risk loci of NSCLC. We also integrated sQTLs into NSCLC GWAS datasets (13,327 affected individuals and 13,328 control individuals) by using splice-transcriptome-wide association study (spTWAS) and identified alternative splicing events in 19 genes that were significantly associated with NSCLC risk. By using functional annotation and experiments, we confirmed an sQTL variant, rs35861926, that reduced the risk of lung adenocarcinoma (rs35861926-T, OR = 0.88, 95% confidence interval [CI]: 0.82–0.93, p = 1.87 × 10−5) by promoting FARP1 exon 20 skipping to downregulate the expression level of the long transcript FARP1 -011. Transcript FARP1 -011 promoted the migration and proliferation of lung adenocarcinoma cells. Overall, our study provided informative lung sQTL resources and insights into the molecular mechanisms linking sQTL variants to NSCLC risk. [Display omitted] This study provided a comprehensive catalog of splicing quantitative trait loci (sQTLs) in lung tissues. Integrative sQTL analysis revealed risk loci for non-small-cell lung cancer. Further experiments confirmed that rs35861926 could reduce lung adenocarcinoma risk by promoting FARP1 exon 20 skipping to downregulate the expression level of transcript FARP1 -011. [ABSTRACT FROM AUTHOR]