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  • Laajala, EssiTurku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; InFLAMES Research Flagship Center, University of Turku, Turku Finland; Turku Doctoral Programme of Molecular Medicine, University of Turku, Turku, Finland; Department of Computer Science, Aalto University, Espoo, Finland (author)

Permutation-based significance analysis reduces the type 1 error rate in bisulfite sequencing data analysis of human umbilical cord blood samples

  • Article/chapterEnglish2022

Publisher, publication year, extent ...

  • 2022-03-04
  • Taylor & Francis,2022
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:oru-97835
  • https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-97835URI
  • https://doi.org/10.1080/15592294.2022.2044127DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Funding agencies:InFLAMES Flagship Programme of the Academy of Finland 337530Business FinlandJuvenile Diabetes Research FoundationSigrid Juselius FoundationJane and Aatos Erkko FoundationFinnish Diabetes FoundationFinnish Cancer FoundationEFSDPediatric Research FoundationTurku University Hospital Special Governmental GrantsTurku Doctoral Programme of Molecular Medicine (TuDMM)Finnish Cultural FoundationFinnish IT center for scienceKyllikki and Uolevi Lehikoinen Foundation 
  • DNA methylation patterns are largely established in-utero and might mediate the impacts of in-utero conditions on later health outcomes. Associations between perinatal DNA methylation marks and pregnancy-related variables, such as maternal age and gestational weight gain, have been earlier studied with methylation microarrays, which typically cover less than 2% of human CpG sites. To detect such associations outside these regions, we chose the bisulphite sequencing approach. We collected and curated clinical data on 200 newborn infants; whose umbilical cord blood samples were analysed with the reduced representation bisulphite sequencing (RRBS) method. A generalized linear mixed-effects model was fit for each high coverage CpG site, followed by spatial and multiple testing adjustment of P values to identify differentially methylated cytosines (DMCs) and regions (DMRs) associated with clinical variables, such as maternal age, mode of delivery, and birth weight. Type 1 error rate was then evaluated with a permutation analysis. We discovered a strong inflation of spatially adjusted P values through the permutation analysis, which we then applied for empirical type 1 error control. The inflation of P values was caused by a common method for spatial adjustment and DMR detection, implemented in tools comb-p and RADMeth. Based on empirically estimated significance thresholds, very little differential methylation was associated with any of the studied clinical variables, other than sex. With this analysis workflow, the sex-associated differentially methylated regions were highly reproducible across studies, technologies, and statistical models.

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  • Halla-Aho, ViiviDepartment of Computer Science, Aalto University, Espoo, Finland (author)
  • Grönroos, ToniTurku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; InFLAMES Research Flagship Center, University of Turku, Turku Finland (author)
  • Kalim, Ubaid UllahTurku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; InFLAMES Research Flagship Center, University of Turku, Turku Finland (author)
  • Vähä-Mäkilä, MariResearch Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland (author)
  • Nurmio, MirjaResearch Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland (author)
  • Kallionpää, HennaTurku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland (author)
  • Lietzén, NiinaTurku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland (author)
  • Mykkänen, JuhaResearch Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland (author)
  • Rasool, OmidTurku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; InFLAMES Research Flagship Center, University of Turku, Turku Finland (author)
  • Toppari, JormaResearch Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland; Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland; Department of Pediatrics, Turku University Hospital, Turku, Finland (author)
  • Oresic, Matej,1967-Örebro universitet,Institutionen för medicinska vetenskaper,Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; InFLAMES Research Flagship Center, University of Turku, Turku Finland(Swepub:oru)moc (author)
  • Knip, MikaelPediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Center for Child Health Research, Tampere University Hospital, Tampere, Finland (author)
  • Lund, RiikkaTurku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland (author)
  • Lahesmaa, RiittaTurku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; InFLAMES Research Flagship Center, University of Turku, Turku Finland; Institute of Biomedicine, University of Turku, Turku, Finland (author)
  • Lähdesmäki, HarriDepartment of Computer Science, Aalto University, Espoo, Finland (author)
  • Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; InFLAMES Research Flagship Center, University of Turku, Turku Finland; Turku Doctoral Programme of Molecular Medicine, University of Turku, Turku, Finland; Department of Computer Science, Aalto University, Espoo, FinlandDepartment of Computer Science, Aalto University, Espoo, Finland (creator_code:org_t)

Related titles

  • In:Epigenetics: Taylor & Francis17:12, s. 1608-16271559-22941559-2308

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