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. 2022 Apr 4;54(4):412–436. doi: 10.1038/s41588-022-01024-z

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 4 — a, Splicing QTL (sQTL)-GWAS integration results. Known TSPAN14 transcripts (GENCODE v38; green, coding sequences; gray, noncoding) plotted with −log₁₀(P) for (1) EADB GWAS stage I (n = 487,511) signal (black), (2) sQTL signal for chr10:80509471–80510106 junction (supporting cryptic exon 1) in the EADB Belgian LCL sQTL catalog (n = 70 individuals, blue) and (3) sQTL signal for chr10:80512269–80512719 junction in the MayoRNAseq TCX sQTL catalog (n = 259 individuals, red); hg38 genomic position is shown above. LCL and brain-based sQTL coloc and sTWAS analyses associate ADD risk with these junctions that suggest cryptic splicing within ADAM10-interacting domain of TSPAN14 (magenta), which was predicted to result in two cryptic exons. b, Long-read sequencing validation of TSPAN14 cryptic exons. Nanopore sequencing results (Supplementary Note) in the zoomed-in region of chr10:80506973–80516400 (cumulative coverage in log₁₀ scale). Pooled LCL cDNA sample sequenced for cDNA Amplicon2 shown in blue. cDNA Amplicon1 was sequenced on biologically independent hippocampal (HPC; n = 16, red), frontal cortex (FC; n = 18, pink) and LCL (n = 59, orange) cDNA samples. Green, canonical exons (8–12); dotted black lines, canonical splicing; blue, cryptic exon 1 (>45 bp); red, cryptic exon 2 (118 bp). All annotated junctions use canonical splice donor (GT) and acceptor (AG) sites. c,d, sQTL-GWAS colocalization plots for chr10:80509471–80510106 (supporting cryptic exon 1) in the EADB Belgian LCL sQTL catalog (n = 70 individuals) (c) and chr10:80512269–80512719 (supporting cryptic exon 2) in the MayoRNAseq TCX sQTL catalog (n = 259 individuals) (d). sQTL signals for the two junctions colocalize with ADD signal (PP4s of 98.8% and 97.4%, respectively), and sTWAS associates with increased preference for the cryptic splicing with decreased ADD risk (sTWAS P = 6.28 × 10⁻¹² and 1.6 × 10⁻¹³, sTWAS Z = −6.9 and −7.4, respectively). y axis, sQTL −log₁₀(P); x axis, EADB GWAS stage I −log₁₀(P). LD r² values calculated within EADB-TOPMed dataset (n = 42,140) based on the lead variant rs6586028 (purple) are indicated on a color scale.