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Functional dissection of inherited non-coding variation influencing multiple myeloma risk
(2022-01-10) Ajore, Ram; Niroula, Abhishek; Pertesi, Maroulio; Cafaro, Caterina; Thodberg, Malte; Went, Molly; Bao, Erik L.; Duran-Lozano, Laura; Lopez de Lapuente Portilla, Aitzkoa; Olafsdottir, Thorunn; Ugidos-Damboriena, Nerea; Magnusson, Olafur; Samur, Mehmet; Lareau, Caleb A.; Halldorsson, Gisli H.; Thorleifsson, Gudmar; Norddahl, Gudmundur L.; Gunnarsdottir, Kristbjorg; Försti, Asta; Goldschmidt, Hartmut; Hemminki, Kari; van Rhee, Frits; Kimber, Scott; Sperling, Adam S.; Kaiser, Martin; Anderson, Kenneth; Jonsdottir, Ingileif; Munshi, Nikhil; Rafnar, Thorunn; Waage, Anders; Weinhold, Niels; Thorsteinsdottir, Unnur; Sankaran, Vijay G.; Stefansson, Kari; Houlston, Richard; Nilsson, Björn; Faculty of Industrial Engineering, Mechanical Engineering and Computer Science; Faculty of Medicine; Health Sciences
Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy.
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Genetic Predisposition to Coronary Artery Disease in Type 2 Diabetes Mellitus
(2020-12-01) Van Zuydam, Natalie R.; Ladenvall, Claes; Voight, Benjamin F.; Strawbridge, Rona J.; Fernandez-Tajes, Juan; Rayner, N. William; Robertson, Neil R.; Mahajan, Anubha; Vlachopoulou, Efthymia; Goel, Anuj; Kleber, Marcus E.; Nelson, Christopher P.; Kwee, Lydia Coulter; Esko, Tõnu; Mihailov, Evelin; Mägi, Reedik; Milani, Lili; Fischer, Krista; Kanoni, Stavroula; Kumar, Jitender; Song, Ci; Hartiala, Jaana A.; Pedersen, Nancy L.; Perola, Markus; Gieger, Christian; Peters, Annette; Qu, Liming; Willems, Sara M.; Doney, Alex S.F.; Morris, Andrew D.; Zheng, Yan; Sesti, Giorgio; Hu, Frank B.; Qi, Lu; Laakso, Markku; Thorsteinsdottir, Unnur; Grallert, Harald; Van Duijn, Cornelia; Reilly, Muredach P.; Ingelsson, Erik; Deloukas, Panos; Kathiresan, Sek; Metspalu, Andres; Shah, Svati H.; Sinisalo, Juha; Salomaa, Veikko; Hamsten, Anders; Samani, Nilesh J.; März, Winfried; Hazen, Stanley L.; Health Sciences
Background: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D). Methods: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D). Results: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background. Conclusions: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.
Verk
Lærdómur
(2022) Magnússon, Magnús Karl; Læknadeild
Verk
Mótun verðuga sjálfsins í menntaskólanum
(2022) Magnúsdóttir, Berglind Rós; Garðarsdóttir, Unnur Edda; Deild menntunar og margbreytileika
Í greininni eru greind þau félagslegu og tilfinningalegu átök sem framhaldsskólanemendur upplifa þegar þau ganga í menntaskóla sem þau hafa lært að sé bæði merkilegri og fínni en þeir staðir sem þau hafa fram að því alið manninn á. Þetta eru nemendur sem eiga ekki uppruna sinn í táknrænum heimi borgaralega hvítflibbans heldur koma úr þorpinu eða sveitinni eða eiga sér bláflibbabakgrunn. Nýtt er hugtakalíkan Bourdieu til að greina þá hvata sem verða til þegar veruhátt og vettvang skortir samhljóm og það þykir virðingarvert að laga sig að vettvangi. Gagnasöfnun fór fram á árunum 2017-2019 og voru tekin djúpviðtöl við 48 stúdentsefni í 10 framhaldsskólum, þar af fjórir landsbyggðarskólar. Fjórðungur viðmælenda úr hátt skrifuðum skólum reyndist hafa bláflibbauppruna og eru raddir þeirra leiðarstef í greininni. Nemendurnir hafa gert sér far um að taka upp gildi og viðmið sem tíðkast á skólavettvangnum en verða á sama tíma mjög gagnrýnin á lífsmáta og hugmyndir á upprunavettvangi. Þetta ferli getur verið sársaukafullt og markast af andstæðum tilfinningum eins og skömm, stolti, sektarkennd og létti.
Verk
Risk Factors for Diagnosis of Psoriatic Arthritis, Psoriasis, Rheumatoid Arthritis, and Ankylosing Spondylitis : A Set of Parallel Case-control Studies
(2022-01-01) Meer, Elana; Thrastardottir, Telma; Wang, Xingmei; Dubreuil, Maureen; Chen, Yong; Gelfand, Joel M.; Love, Thorvardur J.; Ogdie, Alexis; Faculty of Medicine
Objective. To compare potential risk factors for the diagnosis of psoriatic arthritis (PsA), psoriasis (PsO), rheumatoid arthritis (RA), and ankylosing spondylitis (AS). Methods. Four parallel case-control studies were conducted within The Health Improvement Network using data between 1994 and 2015. Patients with PsA, PsO, RA, or AS were identified using validated code lists and matched to controls on age, sex, practice, and year. Risk factors were selected in the time prior to diagnosis. Multivariable logistic regression models were constructed for each disease using automated stepwise regression to test potential risk factors. Results. Patients with incident PsA (n = 7594), PsO (n = 111,375), RA (n = 28,341), and AS (n = 3253) were identified and matched to 75,930, 1,113,345, 283,226, and 32,530 controls, respectively. Median diagnosis age was 48 (IQR 38–59), 43 (IQR 28–60), 60 (IQR 48–71), and 41 (IQR 32–54) years, respectively. In multivariable models, there were some shared and some differing risk factors across all 4 diseases: PsA was associated with obesity, pharyngitis, and skin infections; PsA and PsO were associated with obesity and moderate alcohol intake; PsA and AS were associated with uveitis; and PsA and RA were associated with preceding gout. Both RA and AS were associated with current smoking, former moderate drinking, anemia, osteoporosis, and inflammatory bowel disease. All shared former or current smoking as a risk factor; statin use was inversely associated with all 4 diseases. Conclusion. Shared and different risk factors for PsA, PsO, RA, and AS were identified. Statin use was inversely associated with all 4 conditions.