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Mismapping of sequencing reads from polymorphic duplications generates spurious trans-eQTLs.

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Τίτλος: Mismapping of sequencing reads from polymorphic duplications generates spurious trans-eQTLs.
Συγγραφείς: Aqil, Alber1 (AUTHOR), Huang, Betty Y.H.1,2 (AUTHOR), Pavlidis, Pavlos3,4 (AUTHOR), McCoy, Rajiv C.1,2 (AUTHOR) rajiv.mccoy@jhu.edu, Gokcumen, Omer1,5 (AUTHOR) gokcumen@gmail.com
Πηγή: American Journal of Human Genetics. Aug2026, Vol. 113 Issue 8, p1604-1617. 14p.
Θεματικοί όροι: *False positive error, *Linkage disequilibrium, *Genomics, *DNA copy number variations, *RNA sequencing, *Locus (Genetics)
Περίληψη: The discovery of trans -acting expression quantitative trait loci (trans -eQTLs) remains plagued by false positives. One unaddressed source of these false positives is polymorphic duplications absent in the reference genome. Specifically, RNA sequencing (RNA-seq) reads from a non-reference gene duplicate have the potential to erroneously map to the single reference copy of the gene. These mismapped RNA-seq reads could generate spurious trans -eQTLs that localize near the insertion site of the non-reference duplicate but appear to regulate the reference copy of the gene. In such scenarios, similarly mismapped DNA-seq reads would create apparent long-range linkage disequilibrium between the spurious trans -eQTL and its target gene's locus. We call this footprint "mismapping linkage disequilibrium" and use it to flag spurious trans -eQTLs. We applied this strategy to published trans -eQTLs from Genotype-Tissue Expression (GTEx) and newly generated trans -eQTLs from MAGE, both already filtered for calls attributable to cross-mappability of RNA-seq reads between reference duplicates. This strategy demonstrated that at least 15.4% and 6.1% of trans -eQTLs in GTEx and MAGE, respectively, are spurious due to non-reference polymorphic duplications. We find that spurious trans -eQTLs are more likely to have large effect sizes. Thus, we expect large-sample studies such as eQTLGen (n > 30,000), which are powered to detect many more small-effect trans -eQTLs, to harbor smaller proportions of spurious trans -eQTLs than smaller studies such as GTEx (n = 838) and MAGE (n = 731). The polymorphic duplication of DUSP22 demonstrates how mismapping linkage disequilibrium can uncover both false-positive trans -eQTLs and trans -acting splicing QTLs (trans -sQTLs). Overall, our study offers a practical metric to improve trans -eQTL filtering. Polymorphic gene duplications absent from the reference genome can generate spurious trans -eQTLs. Specifically, variants tagging the polymorphic duplicate may masquerade as trans -eQTLs regulating the reference gene copy. Here, we develop a method to identify these artifacts in trans -eQTL maps using apparent linkage disequilibrium between putative trans -eQTLs and their target genes. [ABSTRACT FROM AUTHOR]
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Items – Name: Title
  Label: Title
  Group: Ti
  Data: Mismapping of sequencing reads from polymorphic duplications generates spurious trans-eQTLs.
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  Data: <searchLink fieldCode="AR" term="%22Aqil%2C+Alber%22">Aqil, Alber</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Huang%2C+Betty+Y%2EH%2E%22">Huang, Betty Y.H.</searchLink><relatesTo>1,2</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Pavlidis%2C+Pavlos%22">Pavlidis, Pavlos</searchLink><relatesTo>3,4</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22McCoy%2C+Rajiv+C%2E%22">McCoy, Rajiv C.</searchLink><relatesTo>1,2</relatesTo> (AUTHOR)<i> rajiv.mccoy@jhu.edu</i><br /><searchLink fieldCode="AR" term="%22Gokcumen%2C+Omer%22">Gokcumen, Omer</searchLink><relatesTo>1,5</relatesTo> (AUTHOR)<i> gokcumen@gmail.com</i>
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  Data: <searchLink fieldCode="JN" term="%22American+Journal+of+Human+Genetics%22">American Journal of Human Genetics</searchLink>. Aug2026, Vol. 113 Issue 8, p1604-1617. 14p.
– Name: Subject
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  Data: *<searchLink fieldCode="DE" term="%22False+positive+error%22">False positive error</searchLink><br />*<searchLink fieldCode="DE" term="%22Linkage+disequilibrium%22">Linkage disequilibrium</searchLink><br />*<searchLink fieldCode="DE" term="%22Genomics%22">Genomics</searchLink><br />*<searchLink fieldCode="DE" term="%22DNA+copy+number+variations%22">DNA copy number variations</searchLink><br />*<searchLink fieldCode="DE" term="%22RNA+sequencing%22">RNA sequencing</searchLink><br />*<searchLink fieldCode="DE" term="%22Locus+%28Genetics%29%22">Locus (Genetics)</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: The discovery of trans -acting expression quantitative trait loci (trans -eQTLs) remains plagued by false positives. One unaddressed source of these false positives is polymorphic duplications absent in the reference genome. Specifically, RNA sequencing (RNA-seq) reads from a non-reference gene duplicate have the potential to erroneously map to the single reference copy of the gene. These mismapped RNA-seq reads could generate spurious trans -eQTLs that localize near the insertion site of the non-reference duplicate but appear to regulate the reference copy of the gene. In such scenarios, similarly mismapped DNA-seq reads would create apparent long-range linkage disequilibrium between the spurious trans -eQTL and its target gene's locus. We call this footprint "mismapping linkage disequilibrium" and use it to flag spurious trans -eQTLs. We applied this strategy to published trans -eQTLs from Genotype-Tissue Expression (GTEx) and newly generated trans -eQTLs from MAGE, both already filtered for calls attributable to cross-mappability of RNA-seq reads between reference duplicates. This strategy demonstrated that at least 15.4% and 6.1% of trans -eQTLs in GTEx and MAGE, respectively, are spurious due to non-reference polymorphic duplications. We find that spurious trans -eQTLs are more likely to have large effect sizes. Thus, we expect large-sample studies such as eQTLGen (n > 30,000), which are powered to detect many more small-effect trans -eQTLs, to harbor smaller proportions of spurious trans -eQTLs than smaller studies such as GTEx (n = 838) and MAGE (n = 731). The polymorphic duplication of DUSP22 demonstrates how mismapping linkage disequilibrium can uncover both false-positive trans -eQTLs and trans -acting splicing QTLs (trans -sQTLs). Overall, our study offers a practical metric to improve trans -eQTL filtering. Polymorphic gene duplications absent from the reference genome can generate spurious trans -eQTLs. Specifically, variants tagging the polymorphic duplicate may masquerade as trans -eQTLs regulating the reference gene copy. Here, we develop a method to identify these artifacts in trans -eQTL maps using apparent linkage disequilibrium between putative trans -eQTLs and their target genes. [ABSTRACT FROM AUTHOR]
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RecordInfo BibRecord:
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    Identifiers:
      – Type: doi
        Value: 10.1016/j.ajhg.2026.07.004
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 14
        StartPage: 1604
    Subjects:
      – SubjectFull: False positive error
        Type: general
      – SubjectFull: Linkage disequilibrium
        Type: general
      – SubjectFull: Genomics
        Type: general
      – SubjectFull: DNA copy number variations
        Type: general
      – SubjectFull: RNA sequencing
        Type: general
      – SubjectFull: Locus (Genetics)
        Type: general
    Titles:
      – TitleFull: Mismapping of sequencing reads from polymorphic duplications generates spurious trans-eQTLs.
        Type: main
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          Name:
            NameFull: Aqil, Alber
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            NameFull: Huang, Betty Y.H.
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            NameFull: Pavlidis, Pavlos
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            NameFull: McCoy, Rajiv C.
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            NameFull: Gokcumen, Omer
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          Dates:
            – D: 06
              M: 08
              Text: Aug2026
              Type: published
              Y: 2026
          Identifiers:
            – Type: issn-print
              Value: 00029297
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              Value: 113
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              Value: 8
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            – TitleFull: American Journal of Human Genetics
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