TY - JOUR T1 - Bivariate Genome-Wide Association Study of Depressive Symptoms with Type 2 Diabetes and Quantitative Glycemic Traits. JF - Psychosom Med Y1 - 2017 A1 - Haljas, Kadri A1 - Amare, Azmeraw T A1 - Alizadeh, Behrooz Z A1 - Hsu, Yi-Hsiang A1 - Mosley, Thomas A1 - Newman, Anne A1 - Murabito, Joanne A1 - Tiemeier, Henning A1 - Tanaka, Toshiko A1 - van Duijn, Cornelia A1 - Ding, Jingzhong A1 - Llewellyn, David J A1 - Bennett, David A A1 - Terracciano, Antonio A1 - Launer, Lenore A1 - Ladwig, Karl-Heinz A1 - Cornelis, Marylin C A1 - Teumer, Alexander A1 - Grabe, Hans A1 - Kardia, Sharon L R A1 - Ware, Erin B A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Eriksson, Johan G A1 - Groop, Leif A1 - Räikkönen, Katri A1 - Lahti, Jari AB -

OBJECTIVE: Shared genetic background may explain phenotypic associations between depression and Type-2-Diabetes (T2D). We aimed to study, on a genome-wide level, if genetic correlation and pleiotropic loci exist between depressive symptoms and T2D or glycemic traits.

METHODS: We estimated SNP-based heritability and analyzed genetic correlation between depressive symptoms and T2D and glycemic traits with the LD Score Regression (LDSC) by combining summary statistics of previously conducted meta-analyses for depressive symptoms by CHARGE consortium (N = 51,258), T2D by Diagram consortium (N = 34,840 patients and 114,981 controls), fasting glucose, fasting insulin, HOMA-β, and HOMA-IR by MAGIC consortium (N = 58,074). Finally, we investigated pleiotropic loci using a bivariate GWAS approach with summary statistics from GWAS meta-analyses and reported loci with genome-wide significant bivariate association p-value (p < 5x10). Biological annotation and function of significant pleiotropic SNPs were assessed in several databases.

RESULTS: The SNP-based heritability ranged from 0.04 to 0.10 in each individual trait. In the LDSC analyses, depressive symptoms showed no significant genetic correlation with T2D or glycemic traits (p > 0.37). Yet, we identified pleiotropic genetic variations for depressive symptoms and T2D (in the IGF2BP2, CDKAL1, CDKN2B-AS, and PLEKHA1 genes), and fasting glucose (in the MADD, CDKN2B-AS, PEX16, and MTNR1B genes).

CONCLUSIONS: We found no significant overall genetic correlations between depressive symptoms, T2D or glycemic traits suggesting major differences in underlying biology of these traits. Yet, several potential pleiotropic loci were identified between depressive symptoms, T2D and fasting glucose suggesting that previously established phenotypic associations may be partly explained by genetic variation in these specific loci.

ER - TY - JOUR T1 - Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. JF - Nat Commun Y1 - 2018 A1 - Teumer, Alexander A1 - Chaker, Layal A1 - Groeneweg, Stefan A1 - Li, Yong A1 - Di Munno, Celia A1 - Barbieri, Caterina A1 - Schultheiss, Ulla T A1 - Traglia, Michela A1 - Ahluwalia, Tarunveer S A1 - Akiyama, Masato A1 - Appel, Emil Vincent R A1 - Arking, Dan E A1 - Arnold, Alice A1 - Astrup, Arne A1 - Beekman, Marian A1 - Beilby, John P A1 - Bekaert, Sofie A1 - Boerwinkle, Eric A1 - Brown, Suzanne J A1 - De Buyzere, Marc A1 - Campbell, Purdey J A1 - Ceresini, Graziano A1 - Cerqueira, Charlotte A1 - Cucca, Francesco A1 - Deary, Ian J A1 - Deelen, Joris A1 - Eckardt, Kai-Uwe A1 - Ekici, Arif B A1 - Eriksson, Johan G A1 - Ferrrucci, Luigi A1 - Fiers, Tom A1 - Fiorillo, Edoardo A1 - Ford, Ian A1 - Fox, Caroline S A1 - Fuchsberger, Christian A1 - Galesloot, Tessel E A1 - Gieger, Christian A1 - Gögele, Martin A1 - De Grandi, Alessandro A1 - Grarup, Niels A1 - Greiser, Karin Halina A1 - Haljas, Kadri A1 - Hansen, Torben A1 - Harris, Sarah E A1 - van Heemst, Diana A1 - den Heijer, Martin A1 - Hicks, Andrew A A1 - den Hollander, Wouter A1 - Homuth, Georg A1 - Hui, Jennie A1 - Ikram, M Arfan A1 - Ittermann, Till A1 - Jensen, Richard A A1 - Jing, Jiaojiao A1 - Jukema, J Wouter A1 - Kajantie, Eero A1 - Kamatani, Yoichiro A1 - Kasbohm, Elisa A1 - Kaufman, Jean-Marc A1 - Kiemeney, Lambertus A A1 - Kloppenburg, Margreet A1 - Kronenberg, Florian A1 - Kubo, Michiaki A1 - Lahti, Jari A1 - Lapauw, Bruno A1 - Li, Shuo A1 - Liewald, David C M A1 - Lim, Ee Mun A1 - Linneberg, Allan A1 - Marina, Michela A1 - Mascalzoni, Deborah A1 - Matsuda, Koichi A1 - Medenwald, Daniel A1 - Meisinger, Christa A1 - Meulenbelt, Ingrid A1 - De Meyer, Tim A1 - Meyer zu Schwabedissen, Henriette E A1 - Mikolajczyk, Rafael A1 - Moed, Matthijs A1 - Netea-Maier, Romana T A1 - Nolte, Ilja M A1 - Okada, Yukinori A1 - Pala, Mauro A1 - Pattaro, Cristian A1 - Pedersen, Oluf A1 - Petersmann, Astrid A1 - Porcu, Eleonora A1 - Postmus, Iris A1 - Pramstaller, Peter P A1 - Psaty, Bruce M A1 - Ramos, Yolande F M A1 - Rawal, Rajesh A1 - Redmond, Paul A1 - Richards, J Brent A1 - Rietzschel, Ernst R A1 - Rivadeneira, Fernando A1 - Roef, Greet A1 - Rotter, Jerome I A1 - Sala, Cinzia F A1 - Schlessinger, David A1 - Selvin, Elizabeth A1 - Slagboom, P Eline A1 - Soranzo, Nicole A1 - Sørensen, Thorkild I A A1 - Spector, Timothy D A1 - Starr, John M A1 - Stott, David J A1 - Taes, Youri A1 - Taliun, Daniel A1 - Tanaka, Toshiko A1 - Thuesen, Betina A1 - Tiller, Daniel A1 - Toniolo, Daniela A1 - Uitterlinden, André G A1 - Visser, W Edward A1 - Walsh, John P A1 - Wilson, Scott G A1 - Wolffenbuttel, Bruce H R A1 - Yang, Qiong A1 - Zheng, Hou-Feng A1 - Cappola, Anne A1 - Peeters, Robin P A1 - Naitza, Silvia A1 - Völzke, Henry A1 - Sanna, Serena A1 - Köttgen, Anna A1 - Visser, Theo J A1 - Medici, Marco AB -

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

VL - 9 IS - 1 ER -