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1. Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry

Author

Burns, Kharis, Mullin, Benjamin H., Moolhuijsen, Loes M. E., Laisk, Triin, Tyrmi, Jaakko S., Cui, Jinrui, Actkins, Ky’Era V., Louwers, Yvonne V., Davis, Lea K., Dudbridge, Frank, Azziz, Ricardo, Goodarzi, Mark O., Laivuori, Hannele, Mägi, Reedik, Visser, Jenny A., Laven, Joop S. E., Wilson, Scott G., Day, Felix R., and Stuckey, Bronwyn G. A.

Published
2024
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2. Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

Author

Sterenborg, Rosalie B. T. M., Steinbrenner, Inga, Li, Yong, Bujnis, Melissa N., Naito, Tatsuhiko, Marouli, Eirini, Galesloot, Tessel E., Babajide, Oladapo, Andreasen, Laura, Astrup, Arne, Åsvold, Bjørn Olav, Bandinelli, Stefania, Beekman, Marian, Beilby, John P., Bork-Jensen, Jette, Boutin, Thibaud, Brody, Jennifer A., Brown, Suzanne J., Brumpton, Ben, Campbell, Purdey J., Cappola, Anne R., Ceresini, Graziano, Chaker, Layal, Chasman, Daniel I., Concas, Maria Pina, Coutinho de Almeida, Rodrigo, Cross, Simone M., Cucca, Francesco, Deary, Ian J., Kjaergaard, Alisa Devedzic, Echouffo Tcheugui, Justin B., Ellervik, Christina, Eriksson, Johan G., Ferrucci, Luigi, Freudenberg, Jan, Fuchsberger, Christian, Gieger, Christian, Giulianini, Franco, Gögele, Martin, Graham, Sarah E., Grarup, Niels, Gunjača, Ivana, Hansen, Torben, Harding, Barbara N., Harris, Sarah E., Haunsø, Stig, Hayward, Caroline, Hui, Jennie, Ittermann, Till, Jukema, J. Wouter, Kajantie, Eero, Kanters, Jørgen K., Kårhus, Line L., Kiemeney, Lambertus A. L. M., Kloppenburg, Margreet, Kühnel, Brigitte, Lahti, Jari, Langenberg, Claudia, Lapauw, Bruno, Leese, Graham, Li, Shuo, Liewald, David C. M., Linneberg, Allan, Lominchar, Jesus V. T., Luan, Jian’an, Martin, Nicholas G., Matana, Antonela, Meima, Marcel E., Meitinger, Thomas, Meulenbelt, Ingrid, Mitchell, Braxton D., Møllehave, Line T., Mora, Samia, Naitza, Silvia, Nauck, Matthias, Netea-Maier, Romana T., Noordam, Raymond, Nursyifa, Casia, Okada, Yukinori, Onano, Stefano, Papadopoulou, Areti, Palmer, Colin N. A., Pattaro, Cristian, Pedersen, Oluf, Peters, Annette, Pietzner, Maik, Polašek, Ozren, Pramstaller, Peter P., Psaty, Bruce M., Punda, Ante, Ray, Debashree, Redmond, Paul, Richards, J. Brent, Ridker, Paul M., Russ, Tom C., Ryan, Kathleen A., Olesen, Morten Salling, Schultheiss, Ulla T., Selvin, Elizabeth, Siddiqui, Moneeza K., Sidore, Carlo, Slagboom, P. Eline, Sørensen, Thorkild I. A., Soto-Pedre, Enrique, Spector, Tim D., Spedicati, Beatrice, Srinivasan, Sundararajan, Starr, John M., Stott, David J., Tanaka, Toshiko, Torlak, Vesela, Trompet, Stella, Tuhkanen, Johanna, Uitterlinden, André G., van den Akker, Erik B., van den Eynde, Tibbert, van der Klauw, Melanie M., van Heemst, Diana, Verroken, Charlotte, Visser, W. Edward, Vojinovic, Dina, Völzke, Henry, Waldenberger, Melanie, Walsh, John P., Wareham, Nicholas J., Weiss, Stefan, Willer, Cristen J., Wilson, Scott G., Wolffenbuttel, Bruce H. R., Wouters, Hanneke J. C. M., Wright, Margaret J., Yang, Qiong, Zemunik, Tatijana, Zhou, Wei, Zhu, Gu, Zöllner, Sebastian, Smit, Johannes W. A., Peeters, Robin P., Köttgen, Anna, Teumer, Alexander, and Medici, Marco

Published
2024
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4. Enhanced resolution profiling in twins reveals differential methylation signatures of type 2 diabetes with links to its complications

Author

Christiansen, Colette, Potier, Louis, Martin, Tiphaine C., Villicaña, Sergio, Castillo-Fernandez, Juan E., Mangino, Massimo, Menni, Cristina, Tsai, Pei-Chien, Campbell, Purdey J., Mullin, Shelby, Ordoñana, Juan R., Monteagudo, Olga, Sachdev, Perminder S., Mather, Karen A., Trollor, Julian N., Pietilainen, Kirsi H., Ollikainen, Miina, Dalgård, Christine, Kyvik, Kirsten, Christensen, Kaare, van Dongen, Jenny, Willemsen, Gonneke, Boomsma, Dorret I., Magnusson, Patrik K.E., Pedersen, Nancy L., Wilson, Scott G., Grundberg, Elin, Spector, Tim D., and Bell, Jordana T.

Published
2024
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5. Identification of Novel Loci Associated With Hip Shape: A Meta‐Analysis of Genomewide Association Studies

Author

Baird, Denis A, Evans, Daniel S, Kamanu, Frederick K, Gregory, Jennifer S, Saunders, Fiona R, Giuraniuc, Claudiu V, Barr, Rebecca J, Aspden, Richard M, Jenkins, Deborah, Kiel, Douglas P, Orwoll, Eric S, Cummings, Steven R, Lane, Nancy E, Mullin, Benjamin H, Williams, Frances MK, Richards, J Brent, Wilson, Scott G, Spector, Tim D, Faber, Benjamin G, Lawlor, Deborah A, Grundberg, Elin, Ohlsson, Claes, Pettersson‐Kymmer, Ulrika, Capellini, Terence D, Richard, Daniel, Beck, Thomas J, Evans, David M, Paternoster, Lavinia, Karasik, David, and Tobias, Jonathan H

Subjects
Prevention, Genetics, Osteoporosis, Arthritis, Aging, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Musculoskeletal, Animals, Bone Density, Femur Head, Genetic Loci, Genome-Wide Association Study, Hip Fractures, Humans, Linkage Disequilibrium, Longitudinal Studies, Mice, Osteoporotic Fractures, Polymorphism, Single Nucleotide, HIP SHAPE, OSTEOARTHRITIS, HIP FRACTURE RISK, DXA, GWAS, Biological Sciences, Engineering, Medical and Health Sciences, Anatomy & Morphology
Abstract

We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p  0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Published
2019

6. Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects

Author

Medina-Gomez, Carolina, Kemp, John P, Trajanoska, Katerina, Luan, Jian’an, Chesi, Alessandra, Ahluwalia, Tarunveer S, Mook-Kanamori, Dennis O, Ham, Annelies, Hartwig, Fernando P, Evans, Daniel S, Joro, Raimo, Nedeljkovic, Ivana, Zheng, Hou-Feng, Zhu, Kun, Atalay, Mustafa, Liu, Ching-Ti, Nethander, Maria, Broer, Linda, Porleifsson, Gudmar, Mullin, Benjamin H, Handelman, Samuel K, Nalls, Mike A, Jessen, Leon E, Heppe, Denise HM, Richards, J Brent, Wang, Carol, Chawes, Bo, Schraut, Katharina E, Amin, Najaf, Wareham, Nick, Karasik, David, Van der Velde, Nathalie, Ikram, M Arfan, Zemel, Babette S, Zhou, Yanhua, Carlsson, Christian J, Liu, Yongmei, McGuigan, Fiona E, Boer, Cindy G, Bønnelykke, Klaus, Ralston, Stuart H, Robbins, John A, Walsh, John P, Zillikens, M Carola, Langenberg, Claudia, Li-Gao, Ruifang, Williams, Frances MK, Harris, Tamara B, Akesson, Kristina, Jackson, Rebecca D, Sigurdsson, Gunnar, Heijer, Martin den, van der Eerden, Bram CJ, van de Peppel, Jeroen, Spector, Timothy D, Pennell, Craig, Horta, Bernardo L, Felix, Janine F, Zhao, Jing Hua, Wilson, Scott G, de Mutsert, Renée, Bisgaard, Hans, Styrkársdóttir, Unnur, Jaddoe, Vincent W, Orwoll, Eric, Lakka, Timo A, Scott, Robert, Grant, Struan FA, Lorentzon, Mattias, van Duijn, Cornelia M, Wilson, James F, Stefansson, Kari, Psaty, Bruce M, Kiel, Douglas P, Ohlsson, Claes, Ntzani, Evangelia, van Wijnen, Andre J, Forgetta, Vincenzo, Ghanbari, Mohsen, Logan, John G, Williams, Graham R, Bassett, JH Duncan, Croucher, Peter I, Evangelou, Evangelos, Uitterlinden, Andre G, Ackert-Bicknell, Cheryl L, Tobias, Jonathan H, Evans, David M, and Rivadeneira, Fernando

Subjects
Rare Diseases, Aging, Human Genome, Osteoporosis, Clinical Research, Genetics, Aetiology, 2.1 Biological and endogenous factors, Musculoskeletal, Good Health and Well Being, Adolescent, Age Factors, Animals, Bone Density, Child, Child, Preschool, Genetic Loci, Genome-Wide Association Study, Humans, Infant, Infant, Newborn, Mice, Knockout, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable, Regression Analysis, BMD, CREB3L1, ESR1, GWASs, RANKL, age-dependent effects, bone mineral density, fracture, genetic correlation, genome-wide association studies, meta-regression, total-body DXA, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

Published
2018

7. Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

Author

Sterenborg, Rosalie B.T.M., Steinbrenner, Inga, Li, Yong, Bujnis, Melissa N., Naito, Tatsuhiko, Marouli, Eirini, Galesloot, Tessel E., Babajide, Oladapo, Andreasen, Laura, Astrup, Arne, Åsvold, Bjørn Olav, Bandinelli, Stefania, Beekman, Marian, Beilby, John P., Bork-Jensen, Jette, Boutin, Thibaud, Brody, Jennifer A., Brown, Suzanne J., Brumpton, Ben, Campbell, Purdey J., Cappola, Anne R., Ceresini, Graziano, Chaker, Layal, Chasman, Daniel I., Concas, Maria Pina, Coutinho de Almeida, Rodrigo, Cross, Simone M., Cucca, Francesco, Deary, Ian J., Kjaergaard, Alisa Devedzic, Echouffo Tcheugui, Justin B., Ellervik, Christina, Eriksson, Johan G., Ferrucci, Luigi, Freudenberg, Jan, Fuchsberger, Christian, Gieger, Christian, Giulianini, Franco, Gögele, Martin, Graham, Sarah E., Grarup, Niels, Gunjača, Ivana, Hansen, Torben, Harding, Barbara N., Harris, Sarah E., Haunsø, Stig, Hayward, Caroline, Hui, Jennie, Ittermann, Till, Jukema, J. Wouter, Kajantie, Eero, Kanters, Jørgen K., Kårhus, Line L., Kiemeney, Lambertus A.L.M., Kloppenburg, Margreet, Kühnel, Brigitte, Lahti, Jari, Langenberg, Claudia, Lapauw, Bruno, Leese, Graham, Li, Shuo, Liewald, David C.M., Linneberg, Allan, Lominchar, Jesus V.T., Luan, Jian’an, Martin, Nicholas G., Matana, Antonela, Meima, Marcel E., Meitinger, Thomas, Meulenbelt, Ingrid, Mitchell, Braxton D., Møllehave, Line T., Mora, Samia, Naitza, Silvia, Nauck, Matthias, Netea-Maier, Romana T., Noordam, Raymond, Nursyifa, Casia, Okada, Yukinori, Onano, Stefano, Papadopoulou, Areti, Palmer, Colin N.A., Pattaro, Cristian, Pedersen, Oluf, Peters, Annette, Pietzner, Maik, Polašek, Ozren, Pramstaller, Peter P., Psaty, Bruce M., Punda, Ante, Ray, Debashree, Redmond, Paul, Richards, J. Brent, Ridker, Paul M., Russ, Tom C., Ryan, Kathleen A., Olesen, Morten Salling, Schultheiss, Ulla T., Selvin, Elizabeth, Siddiqui, Moneeza K., Sidore, Carlo, Slagboom, P. Eline, Sørensen, Thorkild I.A., Soto-Pedre, Enrique, Spector, Tim D., Spedicati, Beatrice, Srinivasan, Sundararajan, Starr, John M., Stott, David J., Tanaka, Toshiko, Torlak, Vesela, Trompet, Stella, Tuhkanen, Johanna, Uitterlinden, André G., van den Akker, Erik B., van den Eynde, Tibbert, van der Klauw, Melanie M., van Heemst, Diana, Verroken, Charlotte, Visser, W. Edward, Vojinovic, Dina, Völzke, Henry, Waldenberger, Melanie, Walsh, John P., Wareham, Nicholas J., Weiss, Stefan, Willer, Cristen J., Wilson, Scott G., Wolffenbuttel, Bruce H.R., Wouters, Hanneke J.C.M., Wright, Margaret J., Yang, Qiong, Zemunik, Tatijana, Zhou, Wei, Zhu, Gu, Zöllner, Sebastian, Smit, Johannes W.A., Peeters, Robin P., Köttgen, Anna, Teumer, Alexander, Medici, Marco, Sterenborg, Rosalie B.T.M., Steinbrenner, Inga, Li, Yong, Bujnis, Melissa N., Naito, Tatsuhiko, Marouli, Eirini, Galesloot, Tessel E., Babajide, Oladapo, Andreasen, Laura, Astrup, Arne, Åsvold, Bjørn Olav, Bandinelli, Stefania, Beekman, Marian, Beilby, John P., Bork-Jensen, Jette, Boutin, Thibaud, Brody, Jennifer A., Brown, Suzanne J., Brumpton, Ben, Campbell, Purdey J., Cappola, Anne R., Ceresini, Graziano, Chaker, Layal, Chasman, Daniel I., Concas, Maria Pina, Coutinho de Almeida, Rodrigo, Cross, Simone M., Cucca, Francesco, Deary, Ian J., Kjaergaard, Alisa Devedzic, Echouffo Tcheugui, Justin B., Ellervik, Christina, Eriksson, Johan G., Ferrucci, Luigi, Freudenberg, Jan, Fuchsberger, Christian, Gieger, Christian, Giulianini, Franco, Gögele, Martin, Graham, Sarah E., Grarup, Niels, Gunjača, Ivana, Hansen, Torben, Harding, Barbara N., Harris, Sarah E., Haunsø, Stig, Hayward, Caroline, Hui, Jennie, Ittermann, Till, Jukema, J. Wouter, Kajantie, Eero, Kanters, Jørgen K., Kårhus, Line L., Kiemeney, Lambertus A.L.M., Kloppenburg, Margreet, Kühnel, Brigitte, Lahti, Jari, Langenberg, Claudia, Lapauw, Bruno, Leese, Graham, Li, Shuo, Liewald, David C.M., Linneberg, Allan, Lominchar, Jesus V.T., Luan, Jian’an, Martin, Nicholas G., Matana, Antonela, Meima, Marcel E., Meitinger, Thomas, Meulenbelt, Ingrid, Mitchell, Braxton D., Møllehave, Line T., Mora, Samia, Naitza, Silvia, Nauck, Matthias, Netea-Maier, Romana T., Noordam, Raymond, Nursyifa, Casia, Okada, Yukinori, Onano, Stefano, Papadopoulou, Areti, Palmer, Colin N.A., Pattaro, Cristian, Pedersen, Oluf, Peters, Annette, Pietzner, Maik, Polašek, Ozren, Pramstaller, Peter P., Psaty, Bruce M., Punda, Ante, Ray, Debashree, Redmond, Paul, Richards, J. Brent, Ridker, Paul M., Russ, Tom C., Ryan, Kathleen A., Olesen, Morten Salling, Schultheiss, Ulla T., Selvin, Elizabeth, Siddiqui, Moneeza K., Sidore, Carlo, Slagboom, P. Eline, Sørensen, Thorkild I.A., Soto-Pedre, Enrique, Spector, Tim D., Spedicati, Beatrice, Srinivasan, Sundararajan, Starr, John M., Stott, David J., Tanaka, Toshiko, Torlak, Vesela, Trompet, Stella, Tuhkanen, Johanna, Uitterlinden, André G., van den Akker, Erik B., van den Eynde, Tibbert, van der Klauw, Melanie M., van Heemst, Diana, Verroken, Charlotte, Visser, W. Edward, Vojinovic, Dina, Völzke, Henry, Waldenberger, Melanie, Walsh, John P., Wareham, Nicholas J., Weiss, Stefan, Willer, Cristen J., Wilson, Scott G., Wolffenbuttel, Bruce H.R., Wouters, Hanneke J.C.M., Wright, Margaret J., Yang, Qiong, Zemunik, Tatijana, Zhou, Wei, Zhu, Gu, Zöllner, Sebastian, Smit, Johannes W.A., Peeters, Robin P., Köttgen, Anna, Teumer, Alexander, and Medici, Marco

Abstract

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

Published
2024

10. Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium.

Author

Moayyeri, Alireza, Hsu, Yi-Hsiang, Karasik, David, Estrada, Karol, Xiao, Su-Mei, Nielson, Carrie, Srikanth, Priya, Giroux, Sylvie, Wilson, Scott G, Zheng, Hou-Feng, Smith, Albert V, Pye, Stephen R, Leo, Paul J, Teumer, Alexander, Hwang, Joo-Yeon, Ohlsson, Claes, McGuigan, Fiona, Minster, Ryan L, Hayward, Caroline, Olmos, José M, Lyytikäinen, Leo-Pekka, Lewis, Joshua R, Swart, Karin MA, Masi, Laura, Oldmeadow, Chris, Holliday, Elizabeth G, Cheng, Sulin, van Schoor, Natasja M, Harvey, Nicholas C, Kruk, Marcin, del Greco M, Fabiola, Igl, Wilmar, Trummer, Olivia, Grigoriou, Efi, Luben, Robert, Liu, Ching-Ti, Zhou, Yanhua, Oei, Ling, Medina-Gomez, Carolina, Zmuda, Joseph, Tranah, Greg, Brown, Suzanne J, Williams, Frances M, Soranzo, Nicole, Jakobsdottir, Johanna, Siggeirsdottir, Kristin, Holliday, Kate L, Hannemann, Anke, Go, Min Jin, Garcia, Melissa, Polasek, Ozren, Laaksonen, Marika, Zhu, Kun, Enneman, Anke W, McEvoy, Mark, Peel, Roseanne, Sham, Pak Chung, Jaworski, Maciej, Johansson, Åsa, Hicks, Andrew A, Pludowski, Pawel, Scott, Rodney, Dhonukshe-Rutten, Rosalie AM, van der Velde, Nathalie, Kähönen, Mika, Viikari, Jorma S, Sievänen, Harri, Raitakari, Olli T, González-Macías, Jesús, Hernández, Jose L, Mellström, Dan, Ljunggren, Osten, Cho, Yoon Shin, Völker, Uwe, Nauck, Matthias, Homuth, Georg, Völzke, Henry, Haring, Robin, Brown, Matthew A, McCloskey, Eugene, Nicholson, Geoffrey C, Eastell, Richard, Eisman, John A, Jones, Graeme, Reid, Ian R, Dennison, Elaine M, Wark, John, Boonen, Steven, Vanderschueren, Dirk, Wu, Frederick CW, Aspelund, Thor, Richards, J Brent, Bauer, Doug, Hofman, Albert, Khaw, Kay-Tee, Dedoussis, George, Obermayer-Pietsch, Barbara, Gyllensten, Ulf, Pramstaller, Peter P, and Lorenc, Roman S

Subjects
Calcaneus, Humans, Osteoporosis, Genetic Predisposition to Disease, Ultrasonography, Cohort Studies, Bone Density, Polymorphism, Single Nucleotide, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Fractures, Bone, Genome-Wide Association Study, Young Adult, Human Genome, Genetics, Aging, 2.1 Biological and endogenous factors, Aetiology, Musculoskeletal, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

Published
2014

11. Epigenome-wide Association Study Shows Differential DNA Methylation of MDC1, KLF9, and CUTA in Autoimmune Thyroid Disease.

Author

Lafontaine, Nicole, Shore, Christopher J, Campbell, Purdey J, Mullin, Benjamin H, Brown, Suzanne J, Panicker, Vijay, Dudbridge, Frank, Brix, Thomas H, Hegedüs, Laszlo, Wilson, Scott G, Bell, Jordana T, and Walsh, John P

Abstract

Context Autoimmune thyroid disease (AITD) includes Graves disease (GD) and Hashimoto disease (HD), which often run in the same family. AITD etiology is incompletely understood: Genetic factors may account for up to 75% of phenotypic variance, whereas epigenetic effects (including DNA methylation [DNAm]) may contribute to the remaining variance (eg, why some individuals develop GD and others HD). Objective This work aimed to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) comparing GD to HD. Methods Whole-blood DNAm was measured across the genome using the Infinium MethylationEPIC array in 32 Australian patients with GD and 30 with HD (discovery cohort) and 32 Danish patients with GD and 32 with HD (replication cohort). Linear mixed models were used to test for differences in quantile-normalized β values of DNAm between GD and HD and data were later meta-analyzed. Comb-p software was used to identify DMRs. Results We identified epigenome-wide significant differences (P < 9E-8) and replicated (P <.05) 2 DMPs between GD and HD (cg06315208 within MDC1 and cg00049440 within KLF9). We identified and replicated a DMR within CUTA (5 CpGs at 6p21.32). We also identified 64 DMPs and 137 DMRs in the meta-analysis. Conclusion Our study reveals differences in DNAm between GD and HD, which may help explain why some people develop GD and others HD and provide a link to environmental risk factors. Additional research is needed to advance understanding of the role of DNAm in AITD and investigate its prognostic and therapeutic potential. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Epigenome-wide Association Study Shows Differential DNA Methylation of MDC1, KLF9, and CUTA in Autoimmune Thyroid Disease

Author

Lafontaine, Nicole, primary, Shore, Christopher J, additional, Campbell, Purdey J, additional, Mullin, Benjamin H, additional, Brown, Suzanne J, additional, Panicker, Vijay, additional, Dudbridge, Frank, additional, Brix, Thomas H, additional, Hegedüs, Laszlo, additional, Wilson, Scott G, additional, Bell, Jordana T, additional, and Walsh, John P, additional

Published
2023
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13. Leveraging osteoclast genetic regulatory data to identify genes with a role in osteoarthritis

Author

Mullin, Benjamin H, primary, Zhu, Kun, additional, Brown, Suzanne J, additional, Mullin, Shelby, additional, Dudbridge, Frank, additional, Pavlos, Nathan J, additional, Richards, J Brent, additional, Grundberg, Elin, additional, Bell, Jordana T, additional, Zeggini, Eleftheria, additional, Walsh, John P, additional, Xu, Jiake, additional, and Wilson, Scott G, additional

Published
2023
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14. Genetic determinants of thyroid function in children

Author

Mulder, Tessa A, primary, Campbell, Purdey J, additional, Taylor, Peter N, additional, Peeters, Robin P, additional, Wilson, Scott G, additional, Medici, Marco, additional, Dayan, Colin, additional, Jaddoe, Vincent V W, additional, Walsh, John P, additional, Martin, Nicholas G, additional, Tiemeier, Henning, additional, and Korevaar, Tim I M, additional

Published
2023
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15. Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis

Author

Medina-Gomez, Carolina, primary, Mullin, Benjamin H., additional, Chesi, Alessandra, additional, Prijatelj, Vid, additional, Kemp, John P., additional, Shochat-Carvalho, Chen, additional, Trajanoska, Katerina, additional, Wang, Carol, additional, Joro, Raimo, additional, Evans, Tavia E., additional, Schraut, Katharina E., additional, Li-Gao, Ruifang, additional, Ahluwalia, Tarunveer S., additional, Zillikens, M. Carola, additional, Zhu, Kun, additional, Mook-Kanamori, Dennis O., additional, Evans, Daniel S., additional, Nethander, Maria, additional, Knol, Maria J., additional, Thorleifsson, Gudmar, additional, Prokic, Ivana, additional, Zemel, Babette, additional, Broer, Linda, additional, McGuigan, Fiona E., additional, van Schoor, Natasja M., additional, Reppe, Sjur, additional, Pawlak, Mikolaj A., additional, Ralston, Stuart H., additional, van der Velde, Nathalie, additional, Lorentzon, Mattias, additional, Stefansson, Kari, additional, Adams, Hieab H. H., additional, Wilson, Scott G., additional, Ikram, M. Arfan, additional, Walsh, John P., additional, Lakka, Timo A., additional, Gautvik, Kaare M., additional, Wilson, James F., additional, Orwoll, Eric S., additional, van Duijn, Cornelia M., additional, Bønnelykke, Klaus, additional, Uitterlinden, Andre G., additional, Styrkársdóttir, Unnur, additional, Akesson, Kristina E., additional, Spector, Timothy D., additional, Tobias, Jonathan H., additional, Ohlsson, Claes, additional, Felix, Janine F., additional, Bisgaard, Hans, additional, Grant, Struan F. A., additional, Richards, J. Brent, additional, Evans, David M., additional, van der Eerden, Bram, additional, van de Peppel, Jeroen, additional, Ackert-Bicknell, Cheryl, additional, Karasik, David, additional, Kague, Erika, additional, and Rivadeneira, Fernando, additional

Published
2023
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20. Epigenome-Wide Association Study Reveals CpG Sites Associated with Thyroid Function and Regulatory Effects on KLF9

Author

Weihs, Antoine, primary, Chaker, Layal, additional, Martin, Tiphaine C., additional, Braun, Kim V.E., additional, Campbell, Purdey J., additional, Cox, Simon R., additional, Fornage, Myriam, additional, Gieger, Christian, additional, Grabe, Hans J., additional, Grallert, Harald, additional, Harris, Sarah E., additional, Kühnel, Brigitte, additional, Marioni, Riccardo E., additional, Martin, Nicholas G., additional, McCartney, Daniel L., additional, McRae, Allan F., additional, Meisinger, Christa, additional, van Meurs, Joyce B.J., additional, Nano, Jana, additional, Nauck, Matthias, additional, Peters, Annette, additional, Prokisch, Holger, additional, Roden, Michael, additional, Selvin, Elizabeth, additional, Beekman, Marian, additional, van Heemst, Diana, additional, Slagboom, Eline P., additional, Swenson, Brenton R., additional, Tin, Adrienne, additional, Tsai, Pei-Chien, additional, Uitterlinden, Andre, additional, Visser, W. Edward, additional, Völzke, Henry, additional, Waldenberger, Melanie, additional, Walsh, John P., additional, Köttgen, Anna, additional, Wilson, Scott G., additional, Peeters, Robin P., additional, Bell, Jordana T., additional, Medici, Marco, additional, and Teumer, Alexander, additional

Published
2023
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21. Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis

Author

Medina-Gomez, Carolina, Mullin, Benjamin H., Chesi, Alessandra, Prijatelj, Vid, Kemp, John P., Shochat-Carvalho, Chen, Trajanoska, Katerina, Wang, Carol, Joro, Raimo, Evans, Tavia E., Schraut, Katharina E., Li-Gao, Ruifang, Ahluwalia, Tarunveer S., Zillikens, M. Carola, Zhu, Kun, Mook-Kanamori, Dennis O., Evans, Daniel S., Nethander, Maria, Knol, Maria J., Thorleifsson, Gudmar, Prokic, Ivana, Zemel, Babette, Broer, Linda, McGuigan, Fiona E., van Schoor, Natasja M., Reppe, Sjur, Pawlak, Mikolaj A., Ralston, Stuart H., van der Velde, Nathalie, Lorentzon, Mattias, Stefansson, Kari, Adams, Hieab H.H., Wilson, Scott G., Ikram, M. Arfan, Walsh, John P., Lakka, Timo A., Gautvik, Kaare M., Wilson, James F., Orwoll, Eric S., van Duijn, Cornelia M., Bønnelykke, Klaus, Uitterlinden, Andre G., Styrkársdóttir, Unnur, Akesson, Kristina E., Spector, Timothy D., Tobias, Jonathan H., Ohlsson, Claes, Felix, Janine F., Bisgaard, Hans, Grant, Struan F.A., Richards, J. Brent, Evans, David M., van der Eerden, Bram, van de Peppel, Jeroen, Ackert-Bicknell, Cheryl, Karasik, David, Kague, Erika, Rivadeneira, Fernando, Medina-Gomez, Carolina, Mullin, Benjamin H., Chesi, Alessandra, Prijatelj, Vid, Kemp, John P., Shochat-Carvalho, Chen, Trajanoska, Katerina, Wang, Carol, Joro, Raimo, Evans, Tavia E., Schraut, Katharina E., Li-Gao, Ruifang, Ahluwalia, Tarunveer S., Zillikens, M. Carola, Zhu, Kun, Mook-Kanamori, Dennis O., Evans, Daniel S., Nethander, Maria, Knol, Maria J., Thorleifsson, Gudmar, Prokic, Ivana, Zemel, Babette, Broer, Linda, McGuigan, Fiona E., van Schoor, Natasja M., Reppe, Sjur, Pawlak, Mikolaj A., Ralston, Stuart H., van der Velde, Nathalie, Lorentzon, Mattias, Stefansson, Kari, Adams, Hieab H.H., Wilson, Scott G., Ikram, M. Arfan, Walsh, John P., Lakka, Timo A., Gautvik, Kaare M., Wilson, James F., Orwoll, Eric S., van Duijn, Cornelia M., Bønnelykke, Klaus, Uitterlinden, Andre G., Styrkársdóttir, Unnur, Akesson, Kristina E., Spector, Timothy D., Tobias, Jonathan H., Ohlsson, Claes, Felix, Janine F., Bisgaard, Hans, Grant, Struan F.A., Richards, J. Brent, Evans, David M., van der Eerden, Bram, van de Peppel, Jeroen, Ackert-Bicknell, Cheryl, Karasik, David, Kague, Erika, and Rivadeneira, Fernando

Abstract

Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of key genes in bone biology, particularly to intramembranous ossification, not captured at other skeletal sites. We perform a genome-wide association meta-analysis (n ~ 43,800) of SK-BMD, identifying 59 loci, collectively explaining 12.5% of the trait variance. Association signals cluster within gene-sets involved in skeletal development and osteoporosis. Among the four novel loci (ZIC1, PRKAR1A, AZIN1/ATP6V1C1, GLRX3), there are factors implicated in intramembranous ossification and as we show, inherent to craniosynostosis processes. Functional follow-up in zebrafish confirms the importance of ZIC1 on cranial suture patterning. Likewise, we observe abnormal cranial bone initiation that culminates in ectopic sutures and reduced BMD in mosaic atp6v1c1 knockouts. Mosaic prkar1a knockouts present asymmetric bone growth and, conversely, elevated BMD. In light of this evidence linking SK-BMD loci to craniofacial abnormalities, our study provides new insight into the pathophysiology, diagnosis and treatment of skeletal diseases., Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of key genes in bone biology, particularly to intramembranous ossification, not captured at other skeletal sites. We perform a genome-wide association meta-analysis (n ~ 43,800) of SK-BMD, identifying 59 loci, collectively explaining 12.5% of the trait variance. Association signals cluster within gene-sets involved in skeletal development and osteoporosis. Among the four novel loci (ZIC1, PRKAR1A, AZIN1/ATP6V1C1, GLRX3), there are factors implicated in intramembranous ossification and as we show, inherent to craniosynostosis processes. Functional follow-up in zebrafish confirms the importance of ZIC1 on cranial suture patterning. Likewise, we observe abnormal cranial bone initiation that culminates in ectopic sutures and reduced BMD in mosaic atp6v1c1 knockouts. Mosaic prkar1a knockouts present asymmetric bone growth and, conversely, elevated BMD. In light of this evidence linking SK-BMD loci to craniofacial abnormalities, our study provides new insight into the pathophysiology, diagnosis and treatment of skeletal diseases.

Published
2023

22. Genetic determinants of thyroid function in children

Author

Mulder, Tessa A., Campbell, Purdey J., Taylor, Peter N., Peeters, Robin P., Wilson, Scott G., Medici, Marco, Dayan, Colin, Jaddoe, Vincent V.W., Walsh, John P., Martin, Nicholas G., Tiemeier, Henning, Korevaar, Tim I.M., Mulder, Tessa A., Campbell, Purdey J., Taylor, Peter N., Peeters, Robin P., Wilson, Scott G., Medici, Marco, Dayan, Colin, Jaddoe, Vincent V.W., Walsh, John P., Martin, Nicholas G., Tiemeier, Henning, and Korevaar, Tim I.M.

Abstract

OBJECTIVE:Genome-wide association studies in adults have identified 42 loci associated with thyroid stimulating hormone (TSH) and 21 loci associated with free thyroxine (FT4) concentrations. While biologically plausible, age-dependent effects have not been assessed. We aimed to study the association of previously identified genetic determinants of TSH and FT4 with TSH and FT4 concentrations in newborns and (pre)school children. METHODS: We selected participants from three population-based prospective cohorts with data on genetic variants and thyroid function: Generation R (N = 2169 children, mean age 6 years; N = 2388 neonates, the Netherlands), the Avon Longitudinal Study of Parents and Children (ALSPAC; N = 3382, age 7.5 years, United Kingdom), and the Brisbane Longitudinal Twin Study (BLTS; N = 1680, age 12.1 years, Australia). The association of single nucleotide polymorphisms (SNPs) with TSH and FT4 concentrations was studied with multivariable linear regression models. Weighted polygenic risk scores (PRSs) were defined to combine SNP effects.RESULTS:In childhood, 30/60 SNPs were associated with TSH and 11/31 SNPs with FT4 after multiple testing correction. The effect sizes for AADAT, GLIS3, TM4SF4, and VEGFA were notably larger than in adults. The TSH PRS explained 5.3%-8.4% of the variability in TSH concentrations; the FT4 PRS explained 1.5%-4.2% of the variability in FT4 concentrations. Five TSH SNPs and no FT4 SNPs were associated with thyroid function in neonates. CONCLUSIONS: The effects of many known thyroid function SNPs are already apparent in childhood and some might be notably larger in children as compared to adults. These findings provide new knowledge about genetic regulation of thyroid function in early life.

Published
2023

25. sj-pdf-2-cep-10.1177_03331024221139253 - Supplemental material for Shared genetics and causal relationships between migraine and thyroid function traits

Author

Tasnim, Sana, Wilson, Scott G, Walsh, John P, and Nyholt, Dale R

Subjects
FOS: Psychology, FOS: Clinical medicine, 170199 Psychology not elsewhere classified, 110319 Psychiatry (incl. Psychotherapy), 110306 Endocrinology, 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified, 110904 Neurology and Neuromuscular Diseases, Neuroscience
Abstract

Supplemental material, sj-pdf-2-cep-10.1177_03331024221139253 for Shared genetics and causal relationships between migraine and thyroid function traits by Sana Tasnim, Scott G Wilson, John P Walsh, Dale R Nyholt and The International Headache Genetics Consortium (IHGC): for the ICON study group in Cephalalgia

Published
2023
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26. sj-pdf-1-cep-10.1177_03331024221139253 - Supplemental material for Shared genetics and causal relationships between migraine and thyroid function traits

Author

Tasnim, Sana, Wilson, Scott G, Walsh, John P, and Nyholt, Dale R

Subjects
FOS: Psychology, FOS: Clinical medicine, 170199 Psychology not elsewhere classified, 110319 Psychiatry (incl. Psychotherapy), 110306 Endocrinology, 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified, 110904 Neurology and Neuromuscular Diseases, Neuroscience
Abstract

Supplemental material, sj-pdf-1-cep-10.1177_03331024221139253 for Shared genetics and causal relationships between migraine and thyroid function traits by Sana Tasnim, Scott G Wilson, John P Walsh, Dale R Nyholt and The International Headache Genetics Consortium (IHGC): for the ICON study group in Cephalalgia

Published
2023
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29. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Author

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

Published
2018
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30. DNA Methylation in Autoimmune Thyroid Disease.

Author

Lafontaine, Nicole, Wilson, Scott G., and Walsh, John P.

Subjects
DNA methylation, AUTOIMMUNE thyroiditis
Abstract

Graves disease and Hashimoto disease form part of the spectrum of autoimmune thyroid disease (AITD), to which genetic and environmental factors are recognized contributors. Epigenetics provides a potential link between environmental influences, gene expression, and thyroid autoimmunity. DNA methylation (DNAm) is the best studied epigenetic process, and global hypomethylation of leukocyte DNA is reported in several autoimmune disorders. This review summarizes the current understanding of DNAm in AITD. Targeted DNAm studies of blood samples from AITD patients have reported differential DNAm in the promoter regions of several genes implicated in AITD, including TNF, IFNG, IL2RA, IL6, ICAM1, and PTPN22. In many cases, however, the findings await replication and are unsupported by functional studies to support causal roles in AITD pathogenesis. Furthermore, thyroid hormones affect DNAm, and in many studies confounding by reverse causation has not been considered. Recent studies have shown that DNAm patterns in candidate genes including ITGA6, PRKAA2, and DAPK1 differ between AITD patients from regions with different iodine status, providing a potential mechanism for associations between iodine and AITD. Research focus in the field is moving from candidate gene studies to an epigenome-wide approach. Genome-wide methylation studies of AITD patients have demonstrated multiple differentially methylated positions, including some in immunoregulatory genes such as NOTCH1, HLA-DRB1, TNF, and ICAM1. Large, epigenome-wide studies are required to elucidate the pathophysiological role of DNAm in AITD, with the potential to provide novel diagnostic and prognostic biomarkers as well as therapeutic targets. [ABSTRACT FROM AUTHOR]

Published
2023
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32. α-Actinin-3 deficiency is associated with reduced bone mass in human and mouse

Author

Yang, Nan, Schindeler, Aaron, McDonald, Michelle M., Seto, Jane T., Houweling, Peter J., Lek, Monkol, Hogarth, Marshall, Morse, Alyson R., Raftery, Joanna M., Balasuriya, Dominic, MacArthur, Daniel G., Berman, Yemima, Quinlan, Kate GR, Eisman, John A., Nguyen, Tuan V., Center, Jacqueline R., Prince, Richard L., Wilson, Scott G., Zhu, Kathy, Little, David G., and North, Kathryn N.

Published
2011
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35. Shared genetics and causal relationships between migraine and thyroid function traits.

Author

Tasnim, Sana, Wilson, Scott G, Walsh, John P, and Nyholt, Dale R

Subjects
*GENETIC correlations, *MIGRAINE, *GENETICS, *GENOME-wide association studies, *THYROID diseases, *THYROID gland
Abstract

Background: Epidemiological studies have reported a comorbid relationship between migraine and thyroid dysfunction. Methods: We investigated the genetic relationship between migraine and thyroid function traits using genome-wide association study (GWAS) data. Results: We found a significant genetic correlation (r g) with migraine for hypothyroidism (r g = 0.0608), secondary hypothyroidism (r g = 0.195), free thyroxine (fT4) (r g = 0.0772), and hyperthyroidism (r g = –0.1046), but not thyroid stimulating hormone (TSH). Pairwise GWAS analysis revealed two shared loci with TSH and 11 shared loci with fT4. Cross-trait GWAS meta-analysis of migraine identified novel genome-wide significant loci: 17 with hypothyroidism, one with hyperthyroidism, five with secondary hypothyroidism, eight with TSH, and 15 with fT4. Of the genes at these loci, six (RERE, TGFB2, APLF, SLC9B1, SGTB, BTBD16 ; migraine + hypothyroidism), three (GADD45A, PFDN1, RSPH6A ; migraine + TSH), and three (SSBP3, BRD3, TEF ; migraine + fT4) were significant in our gene-based analysis (p Fisher's combined P-value < 2.04 × 10−6). In addition, causal analyses suggested a negative causal relationship between migraine and hyperthyroidism (p = 8.90 × 10−3) and a positive causal relationship between migraine and secondary hypothyroidism (p = 1.30 × 10−3). Conclusion: These findings provide strong evidence for genetic correlation and suggest complex causal relationships between migraine and thyroid traits. [ABSTRACT FROM AUTHOR]

Published
2023
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36. Cross-Trait Genetic Analyses Indicate Pleiotropy and Complex Causal Relationships between Headache and Thyroid Function Traits.

Author

Tasnim, Sana, Wilson, Scott G., Walsh, John P., and Nyholt, Dale R.

Subjects
*GENOME-wide association studies, *GENETIC correlations, *THYROID gland function tests, *THYROID gland, *THYROTROPIN
Abstract

Epidemiological studies have reported a comorbid relationship between headache and thyroid traits; however, little is known about the shared genetics and causality that contributes to this association. We investigated the genetic overlap and associations between headache and thyroid function traits using genome-wide association study (GWAS) data. We found a significant genetic correlation (rg) with headache and hypothyroidism (rg = 0.09, p = 2.00 × 10−4), free thyroxine (fT4) (rg = 0.08, p = 5.50 × 10−3), and hyperthyroidism (rg = −0.14, p = 1.80 × 10−3), a near significant genetic correlation with secondary hypothyroidism (rg = 0.20, p = 5.24 × 10−2), but not with thyroid stimulating hormone (TSH). Pairwise-GWAS analysis revealed six, 14, four and five shared (pleiotropic) loci with headache and hypothyroidism, hyperthyroidism, secondary hypothyroidism, and fT4, respectively. Cross-trait GWAS meta-analysis identified novel genome-wide significant loci for headache: five with hypothyroidism, three with secondary hypothyroidism, 12 with TSH, and nine with fT4. Of the genes at these loci, six (FAF1, TMX2-CTNND1, AARSD1, PLCD3, ZNF652, and C20orf203; headache-TSH) and six (HMGB1P45, RPL30P1, ZNF462, TMX2-CTNND1, ITPK1, SECISBP2L; headache-fT4) were significant in our gene-based analysis (pFisher's combined p-value < 2.09 × 10−6). Our causal analysis suggested a positive causal relationship between headache and secondary hypothyroidism (p = 3.64 × 10−4). The results also suggest a positive causal relationship between hypothyroidism and headache (p = 2.45 × 10−3) and a negative causal relationship between hyperthyroidism and headache (p = 1.16 × 10−13). These findings suggest a strong evidence base for a genetic correlation and complex causal relationships between headache and thyroid traits. [ABSTRACT FROM AUTHOR]

Published
2023
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37. Genome Wide Association Metanalysis Of Skull Bone Mineral Density Identifies Loci Relevant For Osteoporosis And Craniosynostosis

Author

Medina-Gomez, Carolina, primary, Mullin, Benjamin H., additional, Chesi, Alessandra, additional, Prijatelj, Vid, additional, Kemp, John P., additional, Shochat-Carvalho, Chen, additional, Trajanoska, Katerina, additional, Wang, Carol, additional, Joro, Raimo, additional, Evans, Tavia E., additional, Schraut, Katharina E., additional, Li-Gao, Ruifang, additional, Ahluwalia, Tarunveer S., additional, Zillikens, M. Carola, additional, Zhu, Kun, additional, Mook-Kanamori, Dennis O., additional, Evans, Daniel S., additional, Nethander, Maria, additional, Knol, Maria J., additional, Thorleifsson, Gudmar, additional, Prokic, Ivana, additional, Zemel, Babette, additional, Broer, Linda, additional, van Schoor, Natasja, additional, Reppe, Sjur, additional, Pawlak, Mikolaj A., additional, Ralston, Stuart H., additional, van der Velde, Nathalie, additional, Lorentzon, Mattias, additional, Stefansson, Kari, additional, Adams, Hieab H.H., additional, Wilson, Scott G., additional, Ikram, M. Arfan, additional, Walsh, John P., additional, Lakka, Timo A., additional, Gautvik, Kaare M., additional, Wilson, James F, additional, Orwoll, Eric S., additional, van Duijn, Cornelia M., additional, Bønnelykke, Klaus, additional, Uitterlinden, Andre G., additional, Stykársdóttir, Unnur, additional, Spector, Timothy D., additional, Tobias, Jonathan H, additional, Ohlsson, Claes, additional, Felix, Janine F., additional, Bisgaard, Hans, additional, Grant, Struan F.A., additional, Richards, J. Brent, additional, Evans, David M., additional, van der Eerden, Bram, additional, van de Peppel, Jeroen, additional, Ackert-Bicknell, Cheryl, additional, Karasik, David, additional, Kague, Erika, additional, and Rivadeneira, Fernando, additional

Published
2021
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38. Genome-wide analysis of thyroid function in Australian adolescents highlights SERPINA7 and NCOA3

Author

Nolan, James, primary, Campbell, Purdey J, additional, Brown, Suzanne J, additional, Zhu, Gu, additional, Gordon, Scott, additional, Lim, Ee Mun, additional, Joseph, John, additional, Cross, Simone M, additional, Panicker, Vijay, additional, Medland, Sarah E, additional, Melton, Phillip E, additional, Beilin, Lawrence J, additional, Mori, Trevor A, additional, Mullin, Benjamin H, additional, Pennell, Craig E, additional, Wang, Carol A, additional, Dudbridge, Frank, additional, Walsh, John P, additional, Martin, Nicholas G, additional, and Wilson, Scott G, additional

Published
2021
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39. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

Author

Zheng, Hou-Feng, Forgetta, Vincenzo, Hsu, Yi-Hsiang, Estrada, Karol, Rosello-Diez, Alberto, Leo, Paul J., Dahia, Chitra L., Park-Min, Kyung Hyun, Tobias, Jonathan H., Kooperberg, Charles, Kleinman, Aaron, Styrkarsdottir, Unnur, Liu, Ching-Ti, Uggla, Charlotta, Evans, Daniel S., Nielson, Carrie M., Walter, Klaudia, Pettersson-Kymmer, Ulrika, McCarthy, Shane, Eriksson, Joel, Kwan, Tony, Jhamai, Mila, Trajanoska, Katerina, Memari, Yasin, Min, Josine, Huang, Jie, Danecek, Petr, Wilmot, Beth, Li, Rui, Chou, Wen-Chi, Mokry, Lauren E., Moayyeri, Alireza, Claussnitzer, Melina, Cheng, Chia-Ho, Cheung, Warren, Medina-Gómez, Carolina, Ge, Bing, Chen, Shu-Huang, Choi, Kwangbom, Oei, Ling, Fraser, James, Kraaij, Robert, Hibbs, Matthew A., Gregson, Celia L., Paquette, Denis, Hofman, Albert, Wibom, Carl, Tranah, Gregory J., Marshall, Mhairi, Gardiner, Brooke B., Cremin, Katie, Auer, Paul, Hsu, Li, Ring, Sue, Tung, Joyce Y., Thorleifsson, Gudmar, Enneman, Anke W., van Schoor, Natasja M., de Groot, Lisette C. P. G. M., van der Velde, Nathalie, Melin, Beatrice, Kemp, John P., Christiansen, Claus, Sayers, Adrian, Zhou, Yanhua, Calderari, Sophie, van Rooij, Jeroen, Carlson, Chris, Peters, Ulrike, Berlivet, Soizik, Dostie, Josée, Uitterlinden, Andre G., Williams, Stephen R., Farber, Charles, Grinberg, Daniel, LaCroix, Andrea Z., Haessler, Jeff, Chasman, Daniel I., Giulianini, Franco, Rose, Lynda M., Ridker, Paul M., Eisman, John A., Nguyen, Tuan V., Center, Jacqueline R., Nogues, Xavier, Garcia-Giralt, Natalia, Launer, Lenore L., Gudnason, Vilmunder, Mellström, Dan, Vandenput, Liesbeth, Amin, Najaf, van Duijn, Cornelia M., Karlsson, Magnus K., Ljunggren, Östen, Svensson, Olle, Hallmans, Göran, Rousseau, François, Giroux, Sylvie, Bussière, Johanne, Arp, Pascal P., Koromani, Fjorda, Prince, Richard L., Lewis, Joshua R., Langdahl, Bente L., Hermann, Pernille A., Jensen, Jens-Erik B., Kaptoge, Stephen, Khaw, Kay-Tee, Reeve, Jonathan, Formosa, Melissa M., Xuereb-Anastasi, Angela, Åkesson, Kristina, McGuigan, Fiona E., Garg, Gaurav, Olmos, Jose M., Zarrabeitia, Maria T., Riancho, Jose A., Ralston, Stuart H., Alonso, Nerea, Jiang, Xi, Goltzman, David, Pastinen, Tomi, Grundberg, Elin, Gauguier, Dominique, Orwoll, Eric S., Karasik, David, Davey-Smith, George, Smith, Albert V., Siggeirsdottir, Kristin, Harris, Tamara B., Zillikens, Carola M., van Meurs, Joyce B. J., Thorsteinsdottir, Unnur, Maurano, Matthew T., Timpson, Nicholas J., Soranzo, Nicole, Durbin, Richard, Wilson, Scott G., Ntzani, Evangelia E., Brown, Matthew A., Stefansson, Kari, Hinds, David A., Spector, Tim, Cupples, Adrienne L., Ohlsson, Claes, Greenwood, Celia M. T., Jackson, Rebecca D., Rowe, David W., Loomis, Cynthia A., Evans, David M., Ackert-Bicknell, Cheryl L., Joyner, Alexandra L., Duncan, Emma L., Kiel, Douglas P., Rivadeneira, Fernando, and Richards, Brent J.

Published
2015
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40. The UK10K project identifies rare variants in health and disease

Author

Walter, Klaudia, Min, Josine L., Huang, Jie, Crooks, Lucy, Memari, Yasin, Perry, John R. B., Xu, ChangJiang, Futema, Marta, Lawson, Daniel, Iotchkova, Valentina, Schiffels, Stephan, Hendricks, Audrey E., Danecek, Petr, Li, Rui, Floyd, James, Wain, Louise V., Humphries, Steve E., Barrett, Jeffrey C., Bala, Senduran, Clapham, Peter, Coates, Guy, Cox, Tony, Daly, Allan, Du, Yuanping, Edkins, Sarah, Ellis, Peter, Flicek, Paul, Guo, Xiaosen, Guo, Xueqin, Huang, Liren, Jackson, David K., Joyce, Chris, Keane, Thomas, Kolb-Kokocinski, Anja, Langford, Cordelia, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Maslen, John, McCarthy, Shane, (co-chair), Muddyman, Dawn, Quail, Michael A., Stalker, Jim, (co-chair), Sun, Jianping, Tian, Jing, Wang, Guangbiao, Wang, Jun, Wang, Yu, Wong, Kim, Zhang, Pingbo, Birney, Ewan, Boustred, Chris, Chen, Lu, Clement, Gail, Cocca, Massimiliano, Smith, George Davey, Day, Ian N. M., Day-Williams, Aaron, Down, Thomas, Dunham, Ian, Evans, David M., Gaunt, Tom R., Geihs, Matthias, Hart, Deborah, Howie, Bryan, Hubbard, Tim, Hysi, Pirro, Jamshidi, Yalda, Karczewski, Konrad J., Kemp, John P., Lachance, Genevieve, Lek, Monkol, Lopes, Margarida, MacArthur, Daniel G., Marchini, Jonathan, Mangino, Massimo, Mathieson, Iain, Metrustry, Sarah, Moayyeri, Alireza, Northstone, Kate, Panoutsopoulou, Kalliope, Paternoster, Lavinia, Quaye, Lydia, Richards, Brent J., (co-chair), Ring, Susan, Ritchie, Graham R. S., Shihab, Hashem A., Shin, So-Youn, Small, Kerrin S., Artigas, María Soler, Soranzo, Nicole, (co-chair), Southam, Lorraine, Spector, Timothy D., St Pourcain, Beate, Surdulescu, Gabriela, Tachmazidou, Ioanna, Timpson, Nicholas J., (co-chair), Tobin, Martin D., Valdes, Ana M., Visscher, Peter M., Ward, Kirsten, Wilson, Scott G., Yang, Jian, Zhang, Feng, Zheng, Hou-Feng, Anney, Richard, Ayub, Muhammad, Blackwood, Douglas, Bolton, Patrick F., Breen, Gerome, Collier, David A., Craddock, Nick, Curran, Sarah, Curtis, David, Gallagher, Louise, Geschwind, Daniel, Gurling, Hugh, Holmans, Peter, Lee, Irene, Lönnqvist, Jouko, McGuffin, Peter, McIntosh, Andrew M., McKechanie, Andrew G., McQuillin, Andrew, Morris, James, OʼDonovan, Michael C., Owen, Michael J., (co-chair), Palotie, Aarno, (co-chair), Parr, Jeremy R., Paunio, Tiina, Pietilainen, Olli, Rehnström, Karola, Sharp, Sally I., Skuse, David, St Clair, David, Suvisaari, Jaana, Walters, James T. R., Williams, Hywel J., Barroso, Inês, (co-chair), Bochukova, Elena, Bounds, Rebecca, Dominiczak, Anna, Farooqi, Sadaf I., (co-chair), Keogh, Julia, Marenne, Gaëlle, Morris, Andrew, OʼRahilly, Stephen, Porteous, David J., Smith, Blair H., Wheeler, Eleanor, Al Turki, Saeed, Anderson, Carl A., Antony, Dinu, Beales, Phil, Bentham, Jamie, Bhattacharya, Shoumo, Calissano, Mattia, Carss, Keren, Chatterjee, Krishna, Cirak, Sebahattin, Cosgrove, Catherine, Fitzpatrick, David R., (co-chair), Foley, Reghan A., Franklin, Christopher S., Grozeva, Detelina, Hurles, Matthew E., (co-chair), Mitchison, Hannah M., Muntoni, Francesco, Onoufriadis, Alexandros, Parker, Victoria, Payne, Felicity, Raymond, Lucy F., Roberts, Nicola, Savage, David B., Scambler, Peter, Schmidts, Miriam, Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Spasic-Boskovic, Olivera, Stevens, Elizabeth, van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Williamson, Kathleen A., Wilson, Crispian, Whyte, Tamieka, Ciampi, Antonio, Greenwood, Celia M. T., (co-chair), Oualkacha, Karim, Zeggini, Eleftheria, (co-chair), Bobrow, Martin, Griffin, Heather, Kaye, Jane, (co-chair), Kennedy, Karen, Kent, Alastair, Smee, Carol, Charlton, Ruth, Ekong, Rosemary, Khawaja, Farrah, Lopes, Luis R., Migone, Nicola, Payne, Stewart J., Plagnol, Vincent, (chair), Pollitt, Rebecca C., Povey, Sue, Ridout, Cheryl K., Robinson, Rachel L., Scott, Richard H., Shaw, Adam, Syrris, Petros, Taylor, Rohan, Vandersteen, Anthony M., Durbin, Richard, (chair), Amuzu, Antoinette, Casas, Juan Pablo, Chambers, John C., Dedoussis, George, Gambaro, Giovanni, Gasparini, Paolo, Isaacs, Aaron, Johnson, Jon, Kleber, Marcus E., Kooner, Jaspal S., Langenberg, Claudia, Luan, Jianʼan, Malerba, Giovanni, März, Winfried, Matchan, Angela, Morris, Richard, Nordestgaard, Børge G., Benn, Marianne, Scott, Robert A., Toniolo, Daniela, Traglia, Michela, Tybjaerg-Hansen, Anne, van Duijn, Cornelia M., van Leeuwen, Elisabeth M., Varbo, Anette, Whincup, Peter, Zaza, Gianluigi, and Zhang, Weihua

Published
2015
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43. A locus on chromosome 1p36 is associated with thyrotropin and thyroid function as identified by genome-wide association study

Author

Panicker, Vijay, Wilson, Scott G., Walsh, John P., Richards, Brent, Brown, Suzanne J., Beilby, John P., Bremner, Alexandra P., Surdulescu, Gabriela L., Qweitin, Emad, Gillham-Nasenya, Irina, Soranzo, Nicole, Lim, Ee M., Fletcher, Stephen J., and Spector, Tim D.

Subjects
Population genetics -- Research, Single nucleotide polymorphisms -- Analysis, Thyroid diseases -- Genetic aspects, Thyroid diseases -- Demographic aspects, Thyrotropin -- Genetic aspects, Thyrotropin -- Research, Biological sciences
Abstract

A genome-wide association study of 2,120,505 SNPs in 2014 female twins from the TwinsUK study was performed to identify genetic loci associated with the metabolic phenotypes thyroid hormones which cause thyroid disorders, a common cause of ill health in the community. The study provide evidence for suggestive association of other SNPs with serum TSH, free T4, and free T3 concentrations and provide better insight into the genetic basis of pituitary-thyroid axis function and metabolic regulation.

Published
2010

44. Identification of a role for the ARHGEF3 gene in postmenopausal osteoporosis

Author

Mullin, Ben H., Prince, Richard L., Dick, Ian M., Hart, Deborah J., Spector, Tim D., Dudbridge, Frank, and Wilson, Scott G.

Subjects
Genetic polymorphisms -- Research, Osteoporosis -- Genetic aspects, Postmenopausal women -- Genetic aspects, Whites -- Genetic aspects, Bones -- Density, Bones -- Research, Biological sciences
Abstract

A study was conducted to determine the effect of polymorphisms within the ARHGEF3 gene (situated within 3p14-p21 locus for bone mineral density (BMD)) on bone density in a large, well-described, family-based cohort of postmenopausal women. Results showed that genetic variation in ARHGEF3 plays a significant role in the determination of bone density in Caucasian women and the data implicated the RhoGTPase-RhoGEF pathway in osteoporosis.

Published
2008

45. Genome-wide association scan identifies a prostaglandin-endoperoxide synthase 2 variant involved in risk of knee osteoarthritis

Author

Valdes, Ana M., Loughlin, John, Timms, Kirsten M., van Meurs, Joyce J.B., Southam, Lorraine, Wilson, Scott G, Doherty, Sally, Lories, Rik J., Luyten, Frank P., Gutin, Alexander, Abkevich, Victor, Dongliang Ge, Hofman, Albert, Uitterlinden, Andre G., Hart, Deborah J., Feng Zhang, Zhai, Guangju, Spector, Tim D., Lanchbury, Jerry, Doherty, Michael, and Egli, Rainer J.

Subjects
Osteoarthritis -- Genetic aspects, Single nucleotide polymorphisms -- Analysis, Genomics -- Research, Gene expression -- Analysis, Biological sciences
Abstract

A large-coverage pooled genome-wide association scan (GWAS) of knee osteoarthritis (OA) and the results from successive test of individual most highly associated single-nucleotide polymorphisms (SNPs) in five case-control studies are reported. Findings show that polymorphism in LD with variants affecting the expression of the PTGS2 gene are associated with susceptibility to knee OA in five independent populations and highlight the importance of inflammatory pathways in OA pathogenesis.

Published
2008

46. Complement C5a induces renal injury in diabetic kidney disease by disrupting mitochondrial metabolic agility

Author

Tan, Sih Min, Ziemann, Mark, Thallas-Bonke, Vicki, Snelson, Matthew, Kumar, Vinod, Laskowski, Adrienne, Nguyen, Tuong-Vi, Huynh, Kevin, Clarke, Michele V., Libianto, Renata, Baker, Scott T., Skene, Alison, Power, David A., MacIsaac, Richard J., Henstridge, Darren C., Wetsel, Rick A., El-Osta, Assam, Meikle, Peter J., Wilson, Scott G., Forbes, Josephine M., Cooper, Mark E., Ekinci, Elif I., Woodruff, Trent M., Coughlan, Melinda T., Tan, Sih Min, Ziemann, Mark, Thallas-Bonke, Vicki, Snelson, Matthew, Kumar, Vinod, Laskowski, Adrienne, Nguyen, Tuong-Vi, Huynh, Kevin, Clarke, Michele V., Libianto, Renata, Baker, Scott T., Skene, Alison, Power, David A., MacIsaac, Richard J., Henstridge, Darren C., Wetsel, Rick A., El-Osta, Assam, Meikle, Peter J., Wilson, Scott G., Forbes, Josephine M., Cooper, Mark E., Ekinci, Elif I., Woodruff, Trent M., and Coughlan, Melinda T.

Published
2020

48. Epigenome-Wide Association Study of Thyroid Function Traits Identifies Novel Associations of fT3 With KLF9 and DOT1L

Author

Lafontaine, Nicole, primary, Campbell, Purdey J, additional, Castillo-Fernandez, Juan E, additional, Mullin, Shelby, additional, Lim, Ee Mun, additional, Kendrew, Phillip, additional, Lewer, Michelle, additional, Brown, Suzanne J, additional, Huang, Rae-Chi, additional, Melton, Phillip E, additional, Mori, Trevor A, additional, Beilin, Lawrence J, additional, Dudbridge, Frank, additional, Spector, Tim D, additional, Wright, Margaret J, additional, Martin, Nicholas G, additional, McRae, Allan F, additional, Panicker, Vijay, additional, Zhu, Gu, additional, Walsh, John P, additional, Bell, Jordana T, additional, and Wilson, Scott G, additional

Published
2021
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