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Genomweite Analyse Genetisch Bedingter Strahlenempfindlichkeit in Wismut-Bergarbeitern (Vertragsnr

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Genomweite Analyse Genetisch Bedingter Strahlenempfindlichkeit in Wismut-Bergarbeitern (Vertragsnr Forschungsvorhaben: Genomweite Analyse genetisch bedingter Strahlenempfindlichkeit in Wismut-Bergarbeitern (Vertragsnr. 3615 S 32253) Auftraggeberin: Die Bundesrepublik Deutschland, vertreten durch das Bundesministerium für Umwelt, Naturschutz, Bau und Reaktorsicherheit, dieses vertreten durch den Präsidenten des Bundesamtes für Strahlenschutz Auftragnehmer: Universitätsmedizin Göttingen (UMG) Projektleitung: Prof. Dr. Heike Bickeböller UMG, Institut für Genetische Epidemiologie Wissenschaftlicher Mitarbeiter: Dr. Albert Rosenberger Laufzeit 1.3.2016-28.2.2017 Fachbetreuung BfS: Dr. Maria Gomolka Schussbericht Genomweite Analyse genetisch bedingter Strahlenempfindlichkeit in Wismut-Bergarbeitern – Datenauswertung und Bewertung der Assoziationsanalysen Der Bericht gibt die Auffassung und Meinung des Auftragnehmers wieder und muss nicht mit der Meinung der Auftraggeberin übereinstimmen. Göttingen, den 19.6.2017 BfS-Projekt 3615 S 32253 Schlussbericht 2 Schlussbericht BfS-Projekt 3615 S 32253 Inhalt 1 Kurzfassung ............................................................................................................................ 11 1.1 Hintergrund ........................................................................................................................... 11 1.2 Projektziel .............................................................................................................................. 11 1.3 Ergebnisse .............................................................................................................................. 12 1.4 Zukünftige Arbeiten und Auswahl zu validierender Kandidatengene (AP 3.3) ..................... 13 2 Summary ................................................................................................................................ 15 2.1 Background ............................................................................................................................ 15 2.2 Project Goal ........................................................................................................................... 15 2.3 Results ................................................................................................................................... 16 2.4 Additional project task .......................................................................................................... 17 3 Kurzdarstellung des FE-Vorhabens ........................................................................................ 19 3.1 Aufgabenstellung ................................................................................................................... 19 3.2 Voraussetzungen, unter denen das FE-Vorhaben durchgeführt wurde ............................... 19 3.3 Planung und Ablauf des Vorhabens ...................................................................................... 19 3.4 Wissenschaftlicher und technischer Stand, an den angeknüpft wurde ................................ 21 3.5 Zusammenarbeit mit anderen Stellen ................................................................................... 21 4 Eingehende Darstellung AP1-AP3 .......................................................................................... 23 4.1 Datentransfer und -harmonisierung ..................................................................................... 23 4.1.1 Zusammenführen und Harmonisieren phänotypischer Daten (AP 2.1a) ...................... 23 4.1.2 Deskriptives: Phänotypen .............................................................................................. 23 4.1.3 Zusammenführen und Harmonisieren genomischer Daten (AP 2.1b) .......................... 25 4.1.4 Deskriptives: Genotypen ................................................................................................ 29 4.2 Basismodell ohne Genotypen ................................................................................................ 31 4.2.1 Bestimmung der Gewichtung der Studienteilnehmer aus Nicht-Wismut-Studien ....... 31 4.2.2 Auswahl des besten mehrerer alternativer Basismodelle ............................................. 32 4.2.3 Propensity-Score zur Zusammenfassung der nicht-genomischen Störgrößen ............. 36 4.2.4 Basismodell mit Propensity-Score ................................................................................. 41 4.3 Genomische Blockstruktur .................................................................................................... 43 4.4 Genomische Stratifikation ..................................................................................................... 46 4.4.1 Ergebnis Markersatz I (m=26.600 Zufallsmarker) .......................................................... 47 4.4.2 Ergebnis Markersatz II (m=33.661 Zufallsmarker) ......................................................... 48 4.4.3 Fazit ................................................................................................................................ 49 4.5 Analysemodell für eine Einzelmarker-Assoziationsanalyse .................................................. 51 4.6 Analysemodell für eine Multimarker-Assoziationsanalyse ................................................... 52 4.7 Einschränkungen der Interpretierbarkeit von Parameterschätzern ..................................... 54 4.8 Resultate der Einzelmarker-Assoziationsanalyse (AP 2.1c) ................................................... 57 4.8.1 Signifikanz für den Interaktionseffekt GxE bzw. für den Joint-Test G/GxE .................... 57 4.8.2 Signifikanz gemäß Hybrid-2-Schritt (H2)-Verfahren nach Murcray et al. ...................... 59 4.9 Resultate der Multimarker-Assoziationsanalyse ................................................................... 65 3 BfS-Projekt 3615 S 32253 Schlussbericht 4.9.1 Signifikanz gemäß GxE bzw. für G/GxE (joint test) mit einfacher Bonferroni- Korrektur ........................................................................................................................ 66 4.9.2 Signifikanz gemäß Hybrid-2-Schritt (H2)-Verfahren im taxativen Modell ..................... 68 4.9.3 Signifikanz gemäß Hybrid-2-Schritt (H2)-Verfahren im Modell mit Marker- Auswahl je LD-Block ....................................................................................................... 70 4.10 Übersicht: LD-Blöcke mit mindestens suggestiver Signifikanz .............................................. 73 4.10.1 Modellschätzung LD-Block Nr. 2271 (Chr. 1p31.3; UBE2U) ........................................... 74 4.10.2 Modellschätzung LD-Block Nr. 5078 (Chr. 1q25.3,intergenetischer Bereich) ............... 75 4.10.3 Modellschätzung LD-Block Nr. 33131 (Chr. 5q23.2, intergenetischer Bereich) ............ 76 4.10.4 Modellschätzung LD-Block Nr. 33135 (Chr. 5q23.2; zwischen CSNK1G3 und LINCO1170) .................................................................................................................... 77 4.10.5 Modellschätzung LD-Block Nr. 33137 (Chr. 5q23.2; zwischen CSNK1G3 und LINCO1170) .................................................................................................................... 77 4.10.6 Modellschätzung LD-Blöcke Nr. 33131-33137 (Chr. 5q23.2, nahe CSNK1G3) ............... 78 4.10.7 Modellschätzung LD-Block Nr. 58899 (Chr. 10p13; CUBN) ........................................... 80 4.10.8 Modellschätzung LD-Block Nr. 64068 (Chr. 11p15.1; CD163L1) .................................... 81 4.10.9 Modellschätzung LD-Block Nr. 68621 (Chr. 12p13.31; CD163L1/ACSM4, PEX5) .......... 82 4.10.10 Modellschätzung LD-Blöcke Nr. 68621-68623 (Chr. 12p13.31; CD163L1, LOC101927882, ACSM4) ................................................................................................ 83 4.10.11 Modellschätzung LD-Block Nr. 69267 (Chr. 12p12.1; SOX5, MIR920) ........................... 84 4.10.12 Modellschätzung LD-Blöcke Nr. 69250-69269 (Chr. 12p12.1; SOX5) ............................ 85 4.10.13 Modellschätzung LD-Block Nr. 82003 (Chr.15q25.1, CHRNB4) ..................................... 86 4.10.14 Modellschätzung LD-Blöcke Nr. 82002-82008 (Chr.15q25.1, CHRNA3, CHRNB4) ........ 87 4.10.15 Modellschätzung LD-Block Nr. 82566 (Chr.15q26.1, ST8SIA2, snoU109) ...................... 88 4.10.16 Modellschätzung LD-Block Nr. 91734 (Chr. 18q21.32; LOC107985187, LOC105372156, RP11-325K19.1) ................................................................................... 90 4.11 Gen-Set-Analyse GSA (AP 3) .................................................................................................. 91 4.11.1 Methode: Gen-Set Enrichment Analyse (GSEA) ............................................................ 91 4.11.2 Auswahl von Gen-Sets für die Gen-Set Analyse (AP 3.1) ............................................... 92 4.11.3 Gen-Sets (HGNC Genfamilien und GO-Begriffe), definiert durch in der GWA- Analyse auffällige Gene bzw. LD-Blöcke ........................................................................ 93 4.11.4 Gen-Sets (HGNC Genfamilien), definiert durch publizierte genetische Interaktionen mit einer Radon-Exposition hinsichtlich Lungenkrebs ............................ 95 4.11.5 Gen-Sets (GO-Begriffe), definiert durch progressionsassoziierte Gene, falls diese durch bekannte Wirkmechanismen einer Radon- bzw. Strahlungsbelastung plausible erscheinen .................................................................... 97 4.11.6 Übersicht: Auswahl der Gen-Sets: Genfamilien und Signalwege ................................ 102 4.11.7 GSA Ergebnisse
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