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Germline variants at SOHLH2 influence multiple myeloma risk
(2021-04) Duran-Lozano, Laura; Thorleifsson, Gudmar; Lopez de Lapuente Portilla, Aitzkoa; Niroula, Abhishek; Went, Molly; Thodberg, Malte; Pertesi, Maroulio; Ajore, Ram; Cafaro, Caterina; Olason, Pall I.; Stefansdottir, Lilja; Bragi Walters, G.; Halldorsson, Gisli H.; Turesson, Ingemar; Kaiser, Martin F.; Weinhold, Niels; Abildgaard, Niels; Andersen, Niels Frost; Mellqvist, Ulf Henrik; Waage, Anders; Juul-Vangsted, Annette; Thorsteinsdottir, Unnur; Hansson, Markus; Houlston, Richard; Rafnar, Thorunn; Stefansson, Kari; Nilsson, Björn; Faculty of Industrial Engineering, Mechanical Engineering and Computer Science; Health Sciences
Multiple myeloma (MM) is caused by the uncontrolled, clonal expansion of plasma cells. While there is epidemiological evidence for inherited susceptibility, the molecular basis remains incompletely understood. We report a genome-wide association study totalling 5,320 cases and 422,289 controls from four Nordic populations, and find a novel MM risk variant at SOHLH2 at 13q13.3 (risk allele frequency = 3.5%; odds ratio = 1.38; P = 2.2 × 10−14). This gene encodes a transcription factor involved in gametogenesis that is normally only weakly expressed in plasma cells. The association is represented by 14 variants in linkage disequilibrium. Among these, rs75712673 maps to a genomic region with open chromatin in plasma cells, and upregulates SOHLH2 in this cell type. Moreover, rs75712673 influences transcriptional activity in luciferase assays, and shows a chromatin looping interaction with the SOHLH2 promoter. Our work provides novel insight into MM susceptibility.
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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.
Verk
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.
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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.