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5. Apomorphine-induced reorganization of striato-frontal connectivity in patients with tremor-dominant Parkinson's disease

Author

Salvatore Nigro* a, Cécile Bordier* b, i, Antonio Cerasa c, Rita Nisticò c, Giuseppe Olivadese c, Basilio Vescio d, Maria Giovanna Bianco e, Antonino Fiorillo e, Gaetano Barbagallo f, Marianna Crasà c, Andrea Quattrone f, Maurizio Morelli f, Gennarina Arabia f, Antonio Augimeri d, Carlo Nicolini b, Angelo Bifone b, g, Aldo Quattrone c, and h

Subjects
Male, 0301 basic medicine, Levodopa, Parkinson's disease, Apomorphine, Dopamine agonist, Resting-state, 03 medical and health sciences, fMRI Graph theory, 0302 clinical medicine, Neural Pathways, Tremor, Basal ganglia, medicine, Humans, Single-Blind Method, Resting-state fMRI, Aged, Tremor-dominant Parkinson's disease, Neural correlates of consciousness, Community detection, Graph theory, Resting state fMRI, medicine.diagnostic_test, Electromyography, business.industry, Functional Neuroimaging, Parkinson Disease, Magnetic resonance imaging, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Frontal Lobe, 3. Good health, Neostriatum, 030104 developmental biology, Neurology, Dopamine Agonists, Female, Neurology (clinical), Geriatrics and Gerontology, business, Neuroscience, 030217 neurology & neurosurgery, medicine.drug
Abstract

Introduction Apomorphine is a dopamine agonist used in Parkinson's disease (PD), which matches levodopa in terms of the magnitude of effect on the cardinal motor features, such as tremor and bradykinesia. The beneficial effect of this treatment on PD patients with tremor-dominant has widely been demonstrated, although the underlying neural correlates are unknown. We sought to examine the effects of apomorphine on topological characteristics of resting-state functional connectivity networks in tremor-dominant PD (tdPD) patients. Methods Sixteen tdPD patients were examined using a combined electromyography-functional magnetic resonance imaging approach. Patients were scanned twice following either placebo (subcutaneous injection of 1 mL saline solution) or 1 mg of apomorphine injection. Graph analysis methods were employed to investigate the modular organization of functional connectivity networks before and after drug treatment. Results After injection of apomorphine, evident reduction of tremor symptoms was mirrored by a significant increase in overall connectivity strength and reorganization of the modular structure of the basal ganglia and of the fronto-striatal module. Moreover, we found an increase in the centrality of motor and premotor regions. No differences were found between pre- and post-placebo sessions. Conclusion These results provide new evidence about the effects of apomorphine at a large-scale neural network level showing that drug treatment modifies the brain functional organization of tdPD, increasing the overall resting-state functional connectivity strength, the segregation of striato-frontal regions and the integrative role of motor areas.

Published
2019

6. The power of genetic diversity in genome-wide association studies of lipids

Author

Graham, S.E., Clarke, S.L., Wu, K.H., Kanoni, S., Zajac, G.J.M., Ramdas, S., Surakka, I., Ntalla, I., Vedantam, S., Winkler, T.W., Locke, A.E., Marouli, E., Hwang, M.Y., Han, S., Narita, A., Choudhury, A., Bentley, A.R., Ekoru, K., Verma, A., Trivedi, B., Martin, H.C., Hunt, K.A., Hui, Q., Klarin, D., Zhu, X, Thorleifsson, G., Helgadottir, A., Gudbjartsson, D.F., Holm, H., Olafsson, I., Akiyama, M., Sakaue, S., Terao, C., Kanai, M., Zhou, W., Brumpton, B.M., Rasheed, H., Ruotsalainen, S.E., Havulinna, A.S., Veturi, Y., Feng, Q., Rosenthal, E.A., Lingren, T., Pacheco, J.A., Pendergrass, S.A., Haessler, J., Giulianini, F., Bradford, Y., Miller, J.E., Campbell, A., Lin, K., Millwood, I.Y., Hindy, G., Rasheed, A., Faul, J.D., Zhao, W., Weir, D.R., Turman, C., Huang, H., Graff, M, Mahajan, A., Brown, M.R., Zhang, W., Yu, K., Schmidt, E.M., Pandit, A., Gustafsson, S., Yin, X., Luan, J., Zhao, J.H., Matsuda, F., Jang, H.M., Yoon, K., Medina-Gomez, C., Pitsillides, A., Hottenga, J.J., Willemsen, G., Wood, A.R., Ji, Y., Gao, Z, Haworth, S., Mitchell, R.E., Chai, J.F., Aadahl, M., Yao, J., Manichaikul, A., Warren, H.R., Ramirez, J., Bork-Jensen, J., Kårhus, L.L., Goel, A., Sabater-Lleal, M., Noordam, R., Sidore, C., Fiorillo, E., McDaid, A.F., Marques-Vidal, P., Wielscher, M., Trompet, S., Sattar, N., Galesloot, T.E., Kiemeney, B., Graaf, J. de, Lores de Motta, L., Pauper, M., Hollander, A.I. den, Sun, Y.V., Willer, C.J., Graham, S.E., Clarke, S.L., Wu, K.H., Kanoni, S., Zajac, G.J.M., Ramdas, S., Surakka, I., Ntalla, I., Vedantam, S., Winkler, T.W., Locke, A.E., Marouli, E., Hwang, M.Y., Han, S., Narita, A., Choudhury, A., Bentley, A.R., Ekoru, K., Verma, A., Trivedi, B., Martin, H.C., Hunt, K.A., Hui, Q., Klarin, D., Zhu, X, Thorleifsson, G., Helgadottir, A., Gudbjartsson, D.F., Holm, H., Olafsson, I., Akiyama, M., Sakaue, S., Terao, C., Kanai, M., Zhou, W., Brumpton, B.M., Rasheed, H., Ruotsalainen, S.E., Havulinna, A.S., Veturi, Y., Feng, Q., Rosenthal, E.A., Lingren, T., Pacheco, J.A., Pendergrass, S.A., Haessler, J., Giulianini, F., Bradford, Y., Miller, J.E., Campbell, A., Lin, K., Millwood, I.Y., Hindy, G., Rasheed, A., Faul, J.D., Zhao, W., Weir, D.R., Turman, C., Huang, H., Graff, M, Mahajan, A., Brown, M.R., Zhang, W., Yu, K., Schmidt, E.M., Pandit, A., Gustafsson, S., Yin, X., Luan, J., Zhao, J.H., Matsuda, F., Jang, H.M., Yoon, K., Medina-Gomez, C., Pitsillides, A., Hottenga, J.J., Willemsen, G., Wood, A.R., Ji, Y., Gao, Z, Haworth, S., Mitchell, R.E., Chai, J.F., Aadahl, M., Yao, J., Manichaikul, A., Warren, H.R., Ramirez, J., Bork-Jensen, J., Kårhus, L.L., Goel, A., Sabater-Lleal, M., Noordam, R., Sidore, C., Fiorillo, E., McDaid, A.F., Marques-Vidal, P., Wielscher, M., Trompet, S., Sattar, N., Galesloot, T.E., Kiemeney, B., Graaf, J. de, Lores de Motta, L., Pauper, M., Hollander, A.I. den, Sun, Y.V., and Willer, C.J.

Abstract

Item does not contain fulltext, Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use(1). Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels(2), heart disease remains the leading cause of death worldwide(3). Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS(4-23) have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns(24). Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine(25), we anticipate that increased diversity of participants will lead to more accurate and equitable(26) application of polygenic scores in clinical practice.

Published
2021

7. The power of genetic diversity in genome-wide association studies of lipids

Author

Graham, S. E. (Sarah E.), Clarke, S. L. (Shoa L.), Wu, K. H. (Kuan-Han H.), Kanoni, S. (Stavroula), Zajac, G. J. (Greg J. M.), Ramdas, S. (Shweta), Surakka, I. (Ida), Ntalla, I. (Ioanna), Vedantam, S. (Sailaja), Winkler, T. W. (Thomas W.), Locke, A. E. (Adam E.), Marouli, E. (Eirini), Hwang, M. Y. (Mi Yeong), Han, S. (Sohee), Narita, A. (Akira), Choudhury, A. (Ananyo), Bentley, A. R. (Amy R.), Ekoru, K. (Kenneth), Verma, A. (Anurag), Trivedi, B. (Bhavi), Martin, H. C. (Hilary C.), Hunt, K. A. (Karen A.), Hui, Q. (Qin), Klarin, D. (Derek), Zhu, X. (Xiang), Thorleifsson, G. (Gudmar), Helgadottir, A. (Anna), Gudbjartsson, D. F. (Daniel F.), Holm, H. (Hilma), Olafsson, I. (Isleifur), Akiyama, M. (Masato), Sakaue, S. (Saori), Terao, C. (Chikashi), Kanai, M. (Masahiro), Zhou, W. (Wei), Brumpton, B. M. (Ben M.), Rasheed, H. (Humaira), Ruotsalainen, S. E. (Sanni E.), Havulinna, A. S. (Aki S.), Veturi, Y. (Yogasudha), Feng, Q. (QiPing), Rosenthal, E. A. (Elisabeth A.), Lingren, T. (Todd), Pacheco, J. A. (Jennifer Allen), Pendergrass, S. A. (Sarah A.), Haessler, J. (Jeffrey), Giulianini, F. (Franco), Bradford, Y. (Yuki), Miller, J. E. (Jason E.), Campbell, A. (Archie), Lin, K. (Kuang), Millwood, I. Y. (Iona Y.), Hindy, G. (George), Rasheed, A. (Asif), Faul, J. D. (Jessica D.), Zhao, W. (Wei), Weir, D. R. (David R.), Turman, C. (Constance), Huang, H. (Hongyan), Graff, M. (Mariaelisa), Mahajan, A. (Anubha), Brown, M. R. (Michael R.), Zhang, W. (Weihua), Yu, K. (Ketian), Schmidt, E. M. (Ellen M.), Pandit, A. (Anita), Gustafsson, S. (Stefan), Yin, X. (Xianyong), Luan, J. (Jian'an), Zhao, J.-H. (Jing-Hua), Matsuda, F. (Fumihiko), Jang, H.-M. (Hye-Mi), Yoon, K. (Kyungheon), Medina-Gomez, C. (Carolina), Pitsillides, A. (Achilleas), Hottenga, J. J. (Jouke Jan), Willemsen, G. (Gonneke), Wood, A. R. (Andrew R.), Ji, Y. (Yingji), Gao, Z. (Zishan), Haworth, S. (Simon), Mitchell, R. E. (Ruth E.), Chai, J. F. (Jin Fang), Aadahl, M. (Mette), Yao, J. (Jie), Manichaikul, A. (Ani), Warren, H. R. (Helen R.), Ramirez, J. (Julia), Bork-Jensen, J. (Jette), Karhus, L. L. (Line L.), Goel, A. (Anuj), Sabater-Lleal, M. (Maria), Noordam, R. (Raymond), Sidore, C. (Carlo), Fiorillo, E. (Edoardo), McDaid, A. F. (Aaron F.), Marques-Vidal, P. (Pedro), Wielscher, M. (Matthias), Trompet, S. (Stella), Sattar, N. (Naveed), Mollehave, L. T. (Line T.), Thuesen, B. H. (Betina H.), Munz, M. (Matthias), Zeng, L. (Lingyao), Huang, J. (Jianfeng), Yang, B. (Bin), Poveda, A. (Alaitz), Kurbasic, A. (Azra), Lamina, C. (Claudia), Forer, L. (Lukas), Scholz, M. (Markus), Galesloot, T. E. (Tessel E.), Bradfield, J. P. (Jonathan P.), Daw, E. W. (E. Warwick), Zmuda, J. M. (Joseph M.), Mitchell, J. S. (Jonathan S.), Fuchsberger, C. (Christian), Christensen, H. (Henry), Brody, J. A. (Jennifer A.), Feitosa, M. F. (Mary F.), Wojczynski, M. K. (Mary K.), Preuss, M. (Michael), Mangino, M. (Massimo), Christofidou, P. (Paraskevi), Verweij, N. (Niek), Benjamins, J. W. (Jan W.), Engmann, J. (Jorgen), Kember, R. L. (Rachel L.), Slieker, R. C. (Roderick C.), Lo, K. S. (Ken Sin), Zilhao, N. R. (Nuno R.), Kleber, M. E. (Marcus E.), Delgado, G. E. (Graciela E.), Huo, S. (Shaofeng), Ikeda, D. D. (Daisuke D.), Iha, H. (Hiroyuki), Yang, J. (Jian), Liu, J. (Jun), Leonard, H. L. (Hampton L.), Marten, J. (Jonathan), Schmidt, B. (Borge), Arendt, M. (Marina), Smyth, L. J. (Laura J.), Canadas-Garre, M. (Marisa), Wang, C. (Chaolong), Nakatochi, M. (Masahiro), Wong, A. (Andrew), Hutri-Kahonen, N. (Nina), Sim, X. (Xueling), Xia, R. (Rui), Huerta-Chagoya, A. (Alicia), Fernandez-Lopez, J. C. (Juan Carlos), Lyssenko, V. (Valeriya), Ahmed, M. (Meraj), Jackson, A. U. (Anne U.), Irvin, M. R. (Marguerite R.), Oldmeadow, C. (Christopher), Kim, H.-N. (Han-Na), Ryu, S. (Seungho), Timmers, P. R. (Paul R. H. J.), Arbeeva, L. (Liubov), Dorajoo, R. (Rajkumar), Lange, L. A. (Leslie A.), Chai, X. (Xiaoran), Prasad, G. (Gauri), Lores-Motta, L. (Laura), Pauper, M. (Marc), Long, J. (Jirong), Li, X. (Xiaohui), Theusch, E. (Elizabeth), Takeuchi, F. (Fumihiko), Spracklen, C. N. (Cassandra N.), Loukola, A. (Anu), Bollepalli, S. (Sailalitha), Warner, S. C. (Sophie C.), Wang, Y. X. (Ya Xing), Wei, W. B. (Wen B.), Nutile, T. (Teresa), Ruggiero, D. (Daniela), Sung, Y. J. (Yun Ju), Hung, Y.-J. (Yi-Jen), Chen, S. (Shufeng), Liu, F. (Fangchao), Yang, J. (Jingyun), Kentistou, K. A. (Katherine A.), Gorski, M. (Mathias), Brumat, M. (Marco), Meidtner, K. (Karina), Bielak, L. F. (Lawrence F.), Smith, J. A. (Jennifer A.), Hebbar, P. (Prashantha), Farmaki, A.-E. (Aliki-Eleni), Hofer, E. (Edith), Lin, M. (Maoxuan), Xue, C. (Chao), Zhang, J. (Jifeng), Concas, M. P. (Maria Pina), Vaccargiu, S. (Simona), van der Most, P. J. (Peter J.), Pitkanen, N. (Niina), Cade, B. E. (Brian E.), Lee, J. (Jiwon), van Der Laan, S. W. (Sander W.), Chitrala, K. N. (Kumaraswamy Naidu), Weiss, S. (Stefan), Zimmermann, M. E. (Martina E.), Lee, J. Y. (Jong Young), Choi, H. S. (Hyeok Sun), Nethander, M. (Maria), Freitag-Wolf, S. (Sandra), Southam, L. (Lorraine), Rayner, N. W. (Nigel W.), Wang, C. A. (Carol A.), Lin, S.-Y. (Shih-Yi), Wang, J.-S. (Jun-Sing), Couture, C. (Christian), Lyytikainen, L.-P. (Leo-Pekka), Nikus, K. (Kjell), Cuellar-Partida, G. (Gabriel), Vestergaard, H. (Henrik), Hildalgo, B. (Bertha), Giannakopoulou, O. (Olga), Cai, Q. (Qiuyin), Obura, M. O. (Morgan O.), van Setten, J. (Jessica), Li, X. (Xiaoyin), Schwander, K. (Karen), Terzikhan, N. (Natalie), Shin, J. H. (Jae Hun), Jackson, R. D. (Rebecca D.), Reiner, A. P. (Alexander P.), Martin, L. W. (Lisa Warsinger), Chen, Z. (Zhengming), Li, L. (Liming), Highland, H. M. (Heather M.), Young, K. L. (Kristin L.), Kawaguchi, T. (Takahisa), Thiery, J. (Joachim), Bis, J. C. (Joshua C.), Nadkarni, G. N. (Girish N.), Launer, L. J. (Lenore J.), Li, H. (Huaixing), Nalls, M. A. (Mike A.), Raitakari, O. T. (Olli T.), Ichihara, S. (Sahoko), Wild, S. H. (Sarah H.), Nelson, C. P. (Christopher P.), Campbell, H. (Harry), Jager, S. (Susanne), Nabika, T. (Toru), Al-Mulla, F. (Fahd), Niinikoski, H. (Harri), Braund, P. S. (Peter S.), Kolcic, I. (Ivana), Kovacs, P. (Peter), Giardoglou, T. (Tota), Katsuya, T. (Tomohiro), Bhatti, F. (Fatima), de Kleijn, D. (Dominique), de Borst, G. J. (Gert J.), Kim, E. K. (Eung Kweon), Adams, H. H. (Hieab H. H.), Ikram, M. A. (M. Arfan), Zhu, X. (Xiaofeng), Asselbergs, F. W. (Folkert W.), Kraaijeveld, A. O. (Adriaan O.), Beulens, J. W. (Joline W. J.), Shu, X.-O. (Xiao-Ou), Rallidis, L. S. (Loukianos S.), Pedersen, O. (Oluf), Hansen, T. (Torben), Mitchell, P. (Paul), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Perusse, L. (Louis), Bouchard, C. (Claude), Tonjes, A. (Anke), Chen, Y. I. (Yii-Der Ida), Pennell, C. E. (Craig E.), Mori, T. A. (Trevor A.), Lieb, W. (Wolfgang), Franke, A. (Andre), Ohlsson, C. (Claes), Mellstrom, D. (Dan), Cho, Y. S. (Yoon Shin), Lee, H. (Hyejin), Yuan, J.-M. (Jian-Min), Koh, W.-P. (Woon-Puay), Rhee, S. Y. (Sang Youl), Woo, J.-T. (Jeong-Taek), Heid, I. M. (Iris M.), Stark, K. J. (Klaus J.), Volzke, H. (Henry), Homuth, G. (Georg), Evans, M. K. (Michele K.), Zonderman, A. B. (Alan B.), Polasek, O. (Ozren), Pasterkamp, G. (Gerard), Hoefer, I. E. (Imo E.), Redline, S. (Susan), Pahkala, K. (Katja), Oldehinkel, A. J. (Albertine J.), Snieder, H. (Harold), Biino, G. (Ginevra), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Chen, Y. E. (Y. Eugene), Bandinelli, S. (Stefania), Dedoussis, G. (George), Thanaraj, T. A. (Thangavel Alphonse), Kardia, S. L. (Sharon L. R.), Kato, N. (Norihiro), Schulze, M. B. (Matthias B.), Girotto, G. (Giorgia), Jung, B. (Bettina), Boger, C. A. (Carsten A.), Joshi, P. K. (Peter K.), Bennett, D. A. (David A.), De Jager, P. L. (Philip L.), Lu, X. (Xiangfeng), Mamakou, V. (Vasiliki), Brown, M. (Morris), Caulfield, M. J. (Mark J.), Munroe, P. B. (Patricia B.), Guo, X. (Xiuqing), Ciullo, M. (Marina), Jonas, J. B. (Jost B.), Samani, N. J. (Nilesh J.), Kaprio, J. (Jaakko), Pajukanta, P. (Paivi), Adair, L. S. (Linda S.), Bechayda, S. A. (Sonny Augustin), de Silva, H. J. (H. Janaka), Wickremasinghe, A. R. (Ananda R.), Krauss, R. M. (Ronald M.), Wu, J.-Y. (Jer-Yuarn), Zheng, W. (Wei), den Hollander, A. I. (Anneke, I), Bharadwaj, D. (Dwaipayan), Correa, A. (Adolfo), Wilson, J. G. (James G.), Lind, L. (Lars), Heng, C.-K. (Chew-Kiat), Nelson, A. E. (Amanda E.), Golightly, Y. M. (Yvonne M.), Wilson, J. F. (James F.), Penninx, B. (Brenda), Kim, H.-L. (Hyung-Lae), Attia, J. (John), Scott, R. J. (Rodney J.), Rao, D. C. (D. C.), Arnett, D. K. (Donna K.), Walker, M. (Mark), Koistinen, H. A. (Heikki A.), Chandak, G. R. (Giriraj R.), Yajnik, C. S. (Chittaranjan S.), Mercader, J. M. (Josep M.), Tusie-Luna, T. (Teresa), Aguilar-Salinas, C. A. (Carlos A.), Villalpando, C. G. (Clicerio Gonzalez), Orozco, L. (Lorena), Fornage, M. (Myriam), Tai, E. S. (E. Shyong), van Dam, R. M. (Rob M.), Lehtimaki, T. (Terho), Chaturvedi, N. (Nish), Yokota, M. (Mitsuhiro), Liu, J. (Jianjun), Reilly, D. F. (Dermot F.), McKnight, A. J. (Amy Jayne), Kee, F. (Frank), Jockel, K.-H. (Karl-Heinz), McCarthy, M. I. (Mark, I), Palmer, C. N. (Colin N. A.), Vitart, V. (Veronique), Hayward, C. (Caroline), Simonsick, E. (Eleanor), van Duijn, C. M. (Cornelia M.), Lu, F. (Fan), Qu, J. (Jia), Hishigaki, H. (Haretsugu), Lin, X. (Xu), Marz, W. (Winfried), Parra, E. J. (Esteban J.), Cruz, M. (Miguel), Gudnason, V. (Vilmundur), Tardif, J.-C. (Jean-Claude), Lettre, G. (Guillaume), Elders, P. J. (Petra J. M.), Damrauer, S. M. (Scott M.), Kumari, M. (Meena), Kivimaki, M. (Mika), van der Harst, P. (Pim), Spector, T. D. (Tim D.), Loos, R. J. (Ruth J. F.), Province, M. A. (Michael A.), Psaty, B. M. (Bruce M.), Brandslund, I. (Ivan), Pramstaller, P. P. (Peter P.), Christensen, K. (Kaare), Ripatti, S. (Samuli), Widen, E. (Elisabeth), Hakonarson, H. (Hakon), Grant, S. F. (Struan F. A.), Kiemeney, L. A. (Lambertus A. L. M.), de Graaf, J. (Jacqueline), Loeffler, M. (Markus), Kronenberg, F. (Florian), Gu, D. (Dongfeng), Erdmann, J. (Jeanette), Schunkert, H. (Heribert), Franks, P. W. (Paul W.), Linneberg, A. (Allan), Jukema, J. W. (J. Wouter), Khera, A. V. (Amit, V), Männikkö, M. (Minna), Järvelin, M.-R. (Marjo-Riitta), Kutalik, Z. (Zoltan), Cucca, F. (Francesco), Mook-Kanamori, D. O. (Dennis O.), van Dijk, K. W. (Ko Willems), Watkins, H. (Hugh), Strachan, D. P. (David P.), Grarup, N. (Niels), Sever, P. (Peter), Poulter, N. (Neil), Rotter, J. I. (Jerome, I), Dantoft, T. M. (Thomas M.), Karpe, F. (Fredrik), Neville, M. J. (Matt J.), Timpson, N. J. (Nicholas J.), Cheng, C.-Y. (Ching-Yu), Wong, T.-Y. (Tien-Yin), Khor, C. C. (Chiea Chuen), Sabanayagam, C. (Charumathi), Peters, A. (Annette), Gieger, C. (Christian), Hattersley, A. T. (Andrew T.), Pedersen, N. L. (Nancy L.), Magnusson, P. K. (Patrik K. E.), Boomsma, D. I. (Dorret, I), de Geus, E. J. (Eco J. C.), Cupples, L. A. (L. Adrienne), van Meurs, J. B. (Joyce B. J.), Ghanbari, M. (Mohsen), Rsen, P. G. (Penny Gordon-La), Huang, W. (Wei), Kim, Y. J. (Young Jin), Tabara, Y. (Yasuharu), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Zeggini, E. (Eleftheria), Kuusisto, J. (Johanna), Laakso, M. (Markku), Ingelsson, E. (Erik), Abecasis, G. (Goncalo), Chambers, J. C. (John C.), Kooner, J. S. (Jaspal S.), de Vries, P. S. (Paul S.), Morrison, A. C. (Alanna C.), North, K. E. (Kari E.), Daviglus, M. (Martha), Kraft, P. (Peter), Martin, N. G. (Nicholas G.), Whitfield, J. B. (John B.), Abbas, S. (Shahid), Saleheen, D. (Danish), Walters, R. G. (Robin G.), Holmes, M. V. (Michael, V), Black, C. (Corri), Smith, B. H. (Blair H.), Justice, A. E. (Anne E.), Baras, A. (Aris), Buring, J. E. (Julie E.), Ridker, P. M. (Paul M.), Chasman, D. I. (Daniel, I), Kooperberg, C. (Charles), Wei, W.-Q. (Wei-Qi), Jarvik, G. P. (Gail P.), Namjou, B. (Bahram), Hayes, M. G. (M. Geoffrey), Ritchie, M. D. (Marylyn D.), Jousilahti, P. (Pekka), Salomaa, V. (Veikko), Hveem, K. (Kristian), Asvold, B. O. (Bjorn Olav), Kubo, M. (Michiaki), Kamatani, Y. (Yoichiro), Okada, Y. (Yukinori), Murakami, Y. (Yoshinori), Thorsteinsdottir, U. (Unnur), Stefansson, K. (Kari), Ho, Y.-L. (Yuk-Lam), Lynch, J. A. (Julie A.), Rader, D. J. (Daniel J.), Tsao, P. S. (Philip S.), Chang, K.-M. (Kyong-Mi), Cho, K. (Kelly), O'Donnell, C. J. (Christopher J.), Gaziano, J. M. (John M.), Wilson, P. (Peter), Rotimi, C. N. (Charles N.), Hazelhurst, S. (Scott), Ramsay, M. (Michele), Trembath, R. C. (Richard C.), van Heel, D. A. (David A.), Tamiya, G. (Gen), Yamamoto, M. (Masayuki), Kim, B.-J. (Bong-Jo), Mohlke, K. L. (Karen L.), Frayling, T. M. (Timothy M.), Hirschhorn, J. N. (Joel N.), Kathiresan, S. (Sekar), Boehnke, M. (Michael), Natarajan, P. (Pradeep), Peloso, G. M. (Gina M.), Brown, C. D. (Christopher D.), Morris, A. P. (Andrew P.), Assimes, T. L. (Themistocles L.), Deloukas, P. (Panos), Sun, Y. V. (Yan, V), Willer, C. J. (Cristen J.), Graham, S. E. (Sarah E.), Clarke, S. L. (Shoa L.), Wu, K. H. (Kuan-Han H.), Kanoni, S. (Stavroula), Zajac, G. J. (Greg J. M.), Ramdas, S. (Shweta), Surakka, I. (Ida), Ntalla, I. (Ioanna), Vedantam, S. (Sailaja), Winkler, T. W. (Thomas W.), Locke, A. E. (Adam E.), Marouli, E. (Eirini), Hwang, M. Y. (Mi Yeong), Han, S. (Sohee), Narita, A. (Akira), Choudhury, A. (Ananyo), Bentley, A. R. (Amy R.), Ekoru, K. (Kenneth), Verma, A. (Anurag), Trivedi, B. (Bhavi), Martin, H. C. (Hilary C.), Hunt, K. A. (Karen A.), Hui, Q. (Qin), Klarin, D. (Derek), Zhu, X. (Xiang), Thorleifsson, G. (Gudmar), Helgadottir, A. (Anna), Gudbjartsson, D. F. (Daniel F.), Holm, H. (Hilma), Olafsson, I. (Isleifur), Akiyama, M. (Masato), Sakaue, S. (Saori), Terao, C. (Chikashi), Kanai, M. (Masahiro), Zhou, W. (Wei), Brumpton, B. M. (Ben M.), Rasheed, H. (Humaira), Ruotsalainen, S. E. (Sanni E.), Havulinna, A. S. (Aki S.), Veturi, Y. (Yogasudha), Feng, Q. (QiPing), Rosenthal, E. A. (Elisabeth A.), Lingren, T. (Todd), Pacheco, J. A. (Jennifer Allen), Pendergrass, S. A. (Sarah A.), Haessler, J. (Jeffrey), Giulianini, F. (Franco), Bradford, Y. (Yuki), Miller, J. E. (Jason E.), Campbell, A. (Archie), Lin, K. (Kuang), Millwood, I. Y. (Iona Y.), Hindy, G. (George), Rasheed, A. (Asif), Faul, J. D. (Jessica D.), Zhao, W. (Wei), Weir, D. R. (David R.), Turman, C. (Constance), Huang, H. (Hongyan), Graff, M. (Mariaelisa), Mahajan, A. (Anubha), Brown, M. R. (Michael R.), Zhang, W. (Weihua), Yu, K. (Ketian), Schmidt, E. M. (Ellen M.), Pandit, A. (Anita), Gustafsson, S. (Stefan), Yin, X. (Xianyong), Luan, J. (Jian'an), Zhao, J.-H. (Jing-Hua), Matsuda, F. (Fumihiko), Jang, H.-M. (Hye-Mi), Yoon, K. (Kyungheon), Medina-Gomez, C. (Carolina), Pitsillides, A. (Achilleas), Hottenga, J. J. (Jouke Jan), Willemsen, G. (Gonneke), Wood, A. R. (Andrew R.), Ji, Y. (Yingji), Gao, Z. (Zishan), Haworth, S. (Simon), Mitchell, R. E. (Ruth E.), Chai, J. F. (Jin Fang), Aadahl, M. (Mette), Yao, J. (Jie), Manichaikul, A. (Ani), Warren, H. R. (Helen R.), Ramirez, J. (Julia), Bork-Jensen, J. (Jette), Karhus, L. L. (Line L.), Goel, A. (Anuj), Sabater-Lleal, M. (Maria), Noordam, R. (Raymond), Sidore, C. (Carlo), Fiorillo, E. (Edoardo), McDaid, A. F. (Aaron F.), Marques-Vidal, P. (Pedro), Wielscher, M. (Matthias), Trompet, S. (Stella), Sattar, N. (Naveed), Mollehave, L. T. (Line T.), Thuesen, B. H. (Betina H.), Munz, M. (Matthias), Zeng, L. (Lingyao), Huang, J. (Jianfeng), Yang, B. (Bin), Poveda, A. (Alaitz), Kurbasic, A. (Azra), Lamina, C. (Claudia), Forer, L. (Lukas), Scholz, M. (Markus), Galesloot, T. E. (Tessel E.), Bradfield, J. P. (Jonathan P.), Daw, E. W. (E. Warwick), Zmuda, J. M. (Joseph M.), Mitchell, J. S. (Jonathan S.), Fuchsberger, C. (Christian), Christensen, H. (Henry), Brody, J. A. (Jennifer A.), Feitosa, M. F. (Mary F.), Wojczynski, M. K. (Mary K.), Preuss, M. (Michael), Mangino, M. (Massimo), Christofidou, P. (Paraskevi), Verweij, N. (Niek), Benjamins, J. W. (Jan W.), Engmann, J. (Jorgen), Kember, R. L. (Rachel L.), Slieker, R. C. (Roderick C.), Lo, K. S. (Ken Sin), Zilhao, N. R. (Nuno R.), Kleber, M. E. (Marcus E.), Delgado, G. E. (Graciela E.), Huo, S. (Shaofeng), Ikeda, D. D. (Daisuke D.), Iha, H. (Hiroyuki), Yang, J. (Jian), Liu, J. (Jun), Leonard, H. L. (Hampton L.), Marten, J. (Jonathan), Schmidt, B. (Borge), Arendt, M. (Marina), Smyth, L. J. (Laura J.), Canadas-Garre, M. (Marisa), Wang, C. (Chaolong), Nakatochi, M. (Masahiro), Wong, A. (Andrew), Hutri-Kahonen, N. (Nina), Sim, X. (Xueling), Xia, R. (Rui), Huerta-Chagoya, A. (Alicia), Fernandez-Lopez, J. C. (Juan Carlos), Lyssenko, V. (Valeriya), Ahmed, M. (Meraj), Jackson, A. U. (Anne U.), Irvin, M. R. (Marguerite R.), Oldmeadow, C. (Christopher), Kim, H.-N. (Han-Na), Ryu, S. (Seungho), Timmers, P. R. (Paul R. H. J.), Arbeeva, L. (Liubov), Dorajoo, R. (Rajkumar), Lange, L. A. (Leslie A.), Chai, X. (Xiaoran), Prasad, G. (Gauri), Lores-Motta, L. (Laura), Pauper, M. (Marc), Long, J. (Jirong), Li, X. (Xiaohui), Theusch, E. (Elizabeth), Takeuchi, F. (Fumihiko), Spracklen, C. N. (Cassandra N.), Loukola, A. (Anu), Bollepalli, S. (Sailalitha), Warner, S. C. (Sophie C.), Wang, Y. X. (Ya Xing), Wei, W. B. (Wen B.), Nutile, T. (Teresa), Ruggiero, D. (Daniela), Sung, Y. J. (Yun Ju), Hung, Y.-J. (Yi-Jen), Chen, S. (Shufeng), Liu, F. (Fangchao), Yang, J. (Jingyun), Kentistou, K. A. (Katherine A.), Gorski, M. (Mathias), Brumat, M. (Marco), Meidtner, K. (Karina), Bielak, L. F. (Lawrence F.), Smith, J. A. (Jennifer A.), Hebbar, P. (Prashantha), Farmaki, A.-E. (Aliki-Eleni), Hofer, E. (Edith), Lin, M. (Maoxuan), Xue, C. (Chao), Zhang, J. (Jifeng), Concas, M. P. (Maria Pina), Vaccargiu, S. (Simona), van der Most, P. J. (Peter J.), Pitkanen, N. (Niina), Cade, B. E. (Brian E.), Lee, J. (Jiwon), van Der Laan, S. W. (Sander W.), Chitrala, K. N. (Kumaraswamy Naidu), Weiss, S. (Stefan), Zimmermann, M. E. (Martina E.), Lee, J. Y. (Jong Young), Choi, H. S. (Hyeok Sun), Nethander, M. (Maria), Freitag-Wolf, S. (Sandra), Southam, L. (Lorraine), Rayner, N. W. (Nigel W.), Wang, C. A. (Carol A.), Lin, S.-Y. (Shih-Yi), Wang, J.-S. (Jun-Sing), Couture, C. (Christian), Lyytikainen, L.-P. (Leo-Pekka), Nikus, K. (Kjell), Cuellar-Partida, G. (Gabriel), Vestergaard, H. (Henrik), Hildalgo, B. (Bertha), Giannakopoulou, O. (Olga), Cai, Q. (Qiuyin), Obura, M. O. (Morgan O.), van Setten, J. (Jessica), Li, X. (Xiaoyin), Schwander, K. (Karen), Terzikhan, N. (Natalie), Shin, J. H. (Jae Hun), Jackson, R. D. (Rebecca D.), Reiner, A. P. (Alexander P.), Martin, L. W. (Lisa Warsinger), Chen, Z. (Zhengming), Li, L. (Liming), Highland, H. M. (Heather M.), Young, K. L. (Kristin L.), Kawaguchi, T. (Takahisa), Thiery, J. (Joachim), Bis, J. C. (Joshua C.), Nadkarni, G. N. (Girish N.), Launer, L. J. (Lenore J.), Li, H. (Huaixing), Nalls, M. A. (Mike A.), Raitakari, O. T. (Olli T.), Ichihara, S. (Sahoko), Wild, S. H. (Sarah H.), Nelson, C. P. (Christopher P.), Campbell, H. (Harry), Jager, S. (Susanne), Nabika, T. (Toru), Al-Mulla, F. (Fahd), Niinikoski, H. (Harri), Braund, P. S. (Peter S.), Kolcic, I. (Ivana), Kovacs, P. (Peter), Giardoglou, T. (Tota), Katsuya, T. (Tomohiro), Bhatti, F. (Fatima), de Kleijn, D. (Dominique), de Borst, G. J. (Gert J.), Kim, E. K. (Eung Kweon), Adams, H. H. (Hieab H. H.), Ikram, M. A. (M. Arfan), Zhu, X. (Xiaofeng), Asselbergs, F. W. (Folkert W.), Kraaijeveld, A. O. (Adriaan O.), Beulens, J. W. (Joline W. J.), Shu, X.-O. (Xiao-Ou), Rallidis, L. S. (Loukianos S.), Pedersen, O. (Oluf), Hansen, T. (Torben), Mitchell, P. (Paul), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Perusse, L. (Louis), Bouchard, C. (Claude), Tonjes, A. (Anke), Chen, Y. I. (Yii-Der Ida), Pennell, C. E. (Craig E.), Mori, T. A. (Trevor A.), Lieb, W. (Wolfgang), Franke, A. (Andre), Ohlsson, C. (Claes), Mellstrom, D. (Dan), Cho, Y. S. (Yoon Shin), Lee, H. (Hyejin), Yuan, J.-M. (Jian-Min), Koh, W.-P. (Woon-Puay), Rhee, S. Y. (Sang Youl), Woo, J.-T. (Jeong-Taek), Heid, I. M. (Iris M.), Stark, K. J. (Klaus J.), Volzke, H. (Henry), Homuth, G. (Georg), Evans, M. K. (Michele K.), Zonderman, A. B. (Alan B.), Polasek, O. (Ozren), Pasterkamp, G. (Gerard), Hoefer, I. E. (Imo E.), Redline, S. (Susan), Pahkala, K. (Katja), Oldehinkel, A. J. (Albertine J.), Snieder, H. (Harold), Biino, G. (Ginevra), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Chen, Y. E. (Y. Eugene), Bandinelli, S. (Stefania), Dedoussis, G. (George), Thanaraj, T. A. (Thangavel Alphonse), Kardia, S. L. (Sharon L. R.), Kato, N. (Norihiro), Schulze, M. B. (Matthias B.), Girotto, G. (Giorgia), Jung, B. (Bettina), Boger, C. A. (Carsten A.), Joshi, P. K. (Peter K.), Bennett, D. A. (David A.), De Jager, P. L. (Philip L.), Lu, X. (Xiangfeng), Mamakou, V. (Vasiliki), Brown, M. (Morris), Caulfield, M. J. (Mark J.), Munroe, P. B. (Patricia B.), Guo, X. (Xiuqing), Ciullo, M. (Marina), Jonas, J. B. (Jost B.), Samani, N. J. (Nilesh J.), Kaprio, J. (Jaakko), Pajukanta, P. (Paivi), Adair, L. S. (Linda S.), Bechayda, S. A. (Sonny Augustin), de Silva, H. J. (H. Janaka), Wickremasinghe, A. R. (Ananda R.), Krauss, R. M. (Ronald M.), Wu, J.-Y. (Jer-Yuarn), Zheng, W. (Wei), den Hollander, A. I. (Anneke, I), Bharadwaj, D. (Dwaipayan), Correa, A. (Adolfo), Wilson, J. G. (James G.), Lind, L. (Lars), Heng, C.-K. (Chew-Kiat), Nelson, A. E. (Amanda E.), Golightly, Y. M. (Yvonne M.), Wilson, J. F. (James F.), Penninx, B. (Brenda), Kim, H.-L. (Hyung-Lae), Attia, J. (John), Scott, R. J. (Rodney J.), Rao, D. C. (D. C.), Arnett, D. K. (Donna K.), Walker, M. (Mark), Koistinen, H. A. (Heikki A.), Chandak, G. R. (Giriraj R.), Yajnik, C. S. (Chittaranjan S.), Mercader, J. M. (Josep M.), Tusie-Luna, T. (Teresa), Aguilar-Salinas, C. A. (Carlos A.), Villalpando, C. G. (Clicerio Gonzalez), Orozco, L. (Lorena), Fornage, M. (Myriam), Tai, E. S. (E. Shyong), van Dam, R. M. (Rob M.), Lehtimaki, T. (Terho), Chaturvedi, N. (Nish), Yokota, M. (Mitsuhiro), Liu, J. (Jianjun), Reilly, D. F. (Dermot F.), McKnight, A. J. (Amy Jayne), Kee, F. (Frank), Jockel, K.-H. (Karl-Heinz), McCarthy, M. I. (Mark, I), Palmer, C. N. (Colin N. A.), Vitart, V. (Veronique), Hayward, C. (Caroline), Simonsick, E. (Eleanor), van Duijn, C. M. (Cornelia M.), Lu, F. (Fan), Qu, J. (Jia), Hishigaki, H. (Haretsugu), Lin, X. (Xu), Marz, W. (Winfried), Parra, E. J. (Esteban J.), Cruz, M. (Miguel), Gudnason, V. (Vilmundur), Tardif, J.-C. (Jean-Claude), Lettre, G. (Guillaume), Elders, P. J. (Petra J. M.), Damrauer, S. M. (Scott M.), Kumari, M. (Meena), Kivimaki, M. (Mika), van der Harst, P. (Pim), Spector, T. D. (Tim D.), Loos, R. J. (Ruth J. F.), Province, M. A. (Michael A.), Psaty, B. M. (Bruce M.), Brandslund, I. (Ivan), Pramstaller, P. P. (Peter P.), Christensen, K. (Kaare), Ripatti, S. (Samuli), Widen, E. (Elisabeth), Hakonarson, H. (Hakon), Grant, S. F. (Struan F. A.), Kiemeney, L. A. (Lambertus A. L. M.), de Graaf, J. (Jacqueline), Loeffler, M. (Markus), Kronenberg, F. (Florian), Gu, D. (Dongfeng), Erdmann, J. (Jeanette), Schunkert, H. (Heribert), Franks, P. W. (Paul W.), Linneberg, A. (Allan), Jukema, J. W. (J. Wouter), Khera, A. V. (Amit, V), Männikkö, M. (Minna), Järvelin, M.-R. (Marjo-Riitta), Kutalik, Z. (Zoltan), Cucca, F. (Francesco), Mook-Kanamori, D. O. (Dennis O.), van Dijk, K. W. (Ko Willems), Watkins, H. (Hugh), Strachan, D. P. (David P.), Grarup, N. (Niels), Sever, P. (Peter), Poulter, N. (Neil), Rotter, J. I. (Jerome, I), Dantoft, T. M. (Thomas M.), Karpe, F. (Fredrik), Neville, M. J. (Matt J.), Timpson, N. J. (Nicholas J.), Cheng, C.-Y. (Ching-Yu), Wong, T.-Y. (Tien-Yin), Khor, C. C. (Chiea Chuen), Sabanayagam, C. (Charumathi), Peters, A. (Annette), Gieger, C. (Christian), Hattersley, A. T. (Andrew T.), Pedersen, N. L. (Nancy L.), Magnusson, P. K. (Patrik K. E.), Boomsma, D. I. (Dorret, I), de Geus, E. J. (Eco J. C.), Cupples, L. A. (L. Adrienne), van Meurs, J. B. (Joyce B. J.), Ghanbari, M. (Mohsen), Rsen, P. G. (Penny Gordon-La), Huang, W. (Wei), Kim, Y. J. (Young Jin), Tabara, Y. (Yasuharu), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Zeggini, E. (Eleftheria), Kuusisto, J. (Johanna), Laakso, M. (Markku), Ingelsson, E. (Erik), Abecasis, G. (Goncalo), Chambers, J. C. (John C.), Kooner, J. S. (Jaspal S.), de Vries, P. S. (Paul S.), Morrison, A. C. (Alanna C.), North, K. E. (Kari E.), Daviglus, M. (Martha), Kraft, P. (Peter), Martin, N. G. (Nicholas G.), Whitfield, J. B. (John B.), Abbas, S. (Shahid), Saleheen, D. (Danish), Walters, R. G. (Robin G.), Holmes, M. V. (Michael, V), Black, C. (Corri), Smith, B. H. (Blair H.), Justice, A. E. (Anne E.), Baras, A. (Aris), Buring, J. E. (Julie E.), Ridker, P. M. (Paul M.), Chasman, D. I. (Daniel, I), Kooperberg, C. (Charles), Wei, W.-Q. (Wei-Qi), Jarvik, G. P. (Gail P.), Namjou, B. (Bahram), Hayes, M. G. (M. Geoffrey), Ritchie, M. D. (Marylyn D.), Jousilahti, P. (Pekka), Salomaa, V. (Veikko), Hveem, K. (Kristian), Asvold, B. O. (Bjorn Olav), Kubo, M. (Michiaki), Kamatani, Y. (Yoichiro), Okada, Y. (Yukinori), Murakami, Y. (Yoshinori), Thorsteinsdottir, U. (Unnur), Stefansson, K. (Kari), Ho, Y.-L. (Yuk-Lam), Lynch, J. A. (Julie A.), Rader, D. J. (Daniel J.), Tsao, P. S. (Philip S.), Chang, K.-M. (Kyong-Mi), Cho, K. (Kelly), O'Donnell, C. J. (Christopher J.), Gaziano, J. M. (John M.), Wilson, P. (Peter), Rotimi, C. N. (Charles N.), Hazelhurst, S. (Scott), Ramsay, M. (Michele), Trembath, R. C. (Richard C.), van Heel, D. A. (David A.), Tamiya, G. (Gen), Yamamoto, M. (Masayuki), Kim, B.-J. (Bong-Jo), Mohlke, K. L. (Karen L.), Frayling, T. M. (Timothy M.), Hirschhorn, J. N. (Joel N.), Kathiresan, S. (Sekar), Boehnke, M. (Michael), Natarajan, P. (Pradeep), Peloso, G. M. (Gina M.), Brown, C. D. (Christopher D.), Morris, A. P. (Andrew P.), Assimes, T. L. (Themistocles L.), Deloukas, P. (Panos), Sun, Y. V. (Yan, V), and Willer, C. J. (Cristen J.)

Abstract

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4‐23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26 application of polygenic scores in clinical practice.

Published
2021

11. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Author

Liu, M, Jiang, Y, Wedow, R, Li, Y, Brazel, DM, Chen, F, Datta, G, Davila-Velderrain, J, McGuire, D, Tian, C, Zhan, X, Team, 23Andme Research, Psychiatry, Hunt All-In, Choquet, H, Docherty, AR, Faul, JD, Foerster, JR, Fritsche, LG, Gabrielsen, ME, Gordon, SD, Haessler, J, Hottenga, J-J, Huang, H, Jang, S-K, Jansen, PR, Ling, Y, Mägi, R, Matoba, N, McMahon, G, Mulas, A, Orrù, V, Palviainen, T, Pandit, A, Reginsson, GW, Skogholt, AH, Smith, JA, Taylor, AE, Turman, C, Willemsen, G, Young, H, Young, KA, Zajac, GJM, Zhao, W, Zhou, W, Bjornsdottir, G, Boardman, JD, Boehnke, M, Boomsma, DI, Chen, C, Cucca, F, Davies, GE, Eaton, CB, Ehringer, MA, Esko, T, Fiorillo, E, Gillespie, NA, Gudbjartsson, DF, Haller, T, Harris, KM, Heath, AC, Hewitt, JK, Hickie, IB, Hokanson, JE, Hopfer, CJ, Hunter, DJ, Iacono, WG, Johnson, EO, Kamatani, Y, Kardia, SLR, Keller, MC, Kellis, M, Kooperberg, C, Kraft, P, Krauter, KS, Laakso, M, Lind, PA, Loukola, A, Lutz, SM, Madden, PAF, Martin, NG, McGue, M, McQueen, MB, Medland, SE, Metspalu, A, Mohlke, KL, Nielsen, JB, Okada, Y, Peters, U, Polderman, TJC, Posthuma, D, Reiner, AP, Rice, JP, Rimm, E, Rose, RJ, Runarsdottir, V, Stallings, MC, Stančáková, A, Stefansson, H, Thai, KK, Tindle, HA, Tyrfingsson, T, Wall, TL, Weir, DR, Weisner, C, Whitfield, JB, Winsvold, BS, Yin, J, Zuccolo, L, Bierut, LJ, Hveem, K, Lee, JJ, Munafò, MR, Saccone, NL, Willer, CJ, Cornelis, MC, David, SP, Hinds, DA, Jorgenson, E, Kaprio, J, Stitzel, JA, Stefansson, K, Thorgeirsson, TE, Abecasis, G, Liu, DJ, Vrieze, S, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, APH - Methodology, Human genetics, Amsterdam Reproduction & Development (AR&D), APH - Aging & Later Life, and Human Genetics

Subjects
Male, Netherlands Twin Register (NTR), Smoking/genetics, ved/biology.organism_classification_rank.species, Alcohol, Genome-wide association study, Brain and Behaviour, chemistry.chemical_compound, 0302 clinical medicine, Tobacco Use Disorder/genetics, Tobacco/adverse effects, Genetics, 0303 health sciences, Smoking, Tobacco and Alcohol, public health, Tobacco Use Disorder, Middle Aged, 3. Good health, Phenotype, psychiatric disorders, Genetic Variation/genetics, Meta-analysis, Genome-Wide Association Study/methods, Female, Physical and Mental Health, Risk, Alcohol Drinking, psychology, Biology, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Tobacco, Humans, Model organism, Gene, 030304 developmental biology, Genetic association, ved/biology, Genetic Variation, Alcohol Drinking/genetics, Heritability, chemistry, genome-wide association studies, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6,7,8,9,10,11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures. © 2019. This is the authors’ accepted and refereed manuscript to the article.

Published
2019

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

Author

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

Abstract

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.

Published
2018
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13. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Author

Teumer, A, Chaker, Layal, Groeneweg, Stefan, Li, Yi, Di Munno, Celia, Barbieri, C, Schultheiss, UT, Traglia, M, Ahluwalia, TS, Akiyama, M, Appel, EVR, Arking, DE, Arnold, A, Astrup, A, Beekman, M, Beilby, JP, Bekaert, S, Boerwinkle, E, Brown, SJ, de Buyzere, M, Campbell, PJ, Ceresini, G, Cerqueira, C, Cucca, F, Deary, IJ, Deelen, J, Eckardt, KU, Ekici, AB, Eriksson, JG, Ferrrucci, L, Fiers, T, Fiorillo, E, Ford, I, Fox, CS, Fuchsberger, C, Galesloot, TE, Gieger, C, Gogele, M, De Grandi, A, Grarup, N, Greiser, KH, Haljas, K, Hansen, T, Harris, SE, van Heemst, D, Heijer, M, Hicks, AA, den Hollander, W, Homuth, G, Hui, JN, Ikram, Arfan, Ittermann, T, Jensen, RA, Jing, J, Jukema, JW, Kajalltie, E, Kamatani, Y, Kasbohm, E, Kaufman, JM, Kiemeney, LA, Kloppenburg, M, Kronenberg, F, Kubo, M, Lahti, J, Lapauw, B, Li, S, Liewald, DCM, Lim, EM, Linneberg, A, Marina, M, Mascalzoni, D, Matsuda, K, Medenwald, D, Meisinger, C, Meulenbelt, I, Meyer, T, zu Schwabedissen, HEM, Mikolajczyk, R, Moed, M, Netea-Maier, RT, Nolte, IM, Okadah, Y, Pala, M, Pattaro, C, Pedersen, O, Petersmann, A, Porcu, E, Postmus, I, Pramstaller, PP, Psaty, BM, Ramos, YFM, Rawal, R, Redmond, P, Richards, JB, Rietzschel, ER, Rivadeneira, Fernando, Roef, G, Rotter, JI, Sala, CF, Schlessinger, D, Selvin, E, Slagboom, PE (Eline), Soranzo, N, Sorensen, TIA, Spector, TD, Starr, JM, Stott, DJ, Taes, Y, Taliun, D, Tanaka, T, Thuesen, B, Tiller, D, Toniolo, D, Uitterlinden, André, Visser, Edward, Walsh, JP, Wilson, SG, Wolffenbuttel, BHR, Yang, Q, Zheng, HF, Cappola, A, Peeters, Robin, Naitza, S, Volzke, H, Sanna, S, Kottgen, A, Visser, Theo, Medici, Marco, Teumer, A, Chaker, Layal, Groeneweg, Stefan, Li, Yi, Di Munno, Celia, Barbieri, C, Schultheiss, UT, Traglia, M, Ahluwalia, TS, Akiyama, M, Appel, EVR, Arking, DE, Arnold, A, Astrup, A, Beekman, M, Beilby, JP, Bekaert, S, Boerwinkle, E, Brown, SJ, de Buyzere, M, Campbell, PJ, Ceresini, G, Cerqueira, C, Cucca, F, Deary, IJ, Deelen, J, Eckardt, KU, Ekici, AB, Eriksson, JG, Ferrrucci, L, Fiers, T, Fiorillo, E, Ford, I, Fox, CS, Fuchsberger, C, Galesloot, TE, Gieger, C, Gogele, M, De Grandi, A, Grarup, N, Greiser, KH, Haljas, K, Hansen, T, Harris, SE, van Heemst, D, Heijer, M, Hicks, AA, den Hollander, W, Homuth, G, Hui, JN, Ikram, Arfan, Ittermann, T, Jensen, RA, Jing, J, Jukema, JW, Kajalltie, E, Kamatani, Y, Kasbohm, E, Kaufman, JM, Kiemeney, LA, Kloppenburg, M, Kronenberg, F, Kubo, M, Lahti, J, Lapauw, B, Li, S, Liewald, DCM, Lim, EM, Linneberg, A, Marina, M, Mascalzoni, D, Matsuda, K, Medenwald, D, Meisinger, C, Meulenbelt, I, Meyer, T, zu Schwabedissen, HEM, Mikolajczyk, R, Moed, M, Netea-Maier, RT, Nolte, IM, Okadah, Y, Pala, M, Pattaro, C, Pedersen, O, Petersmann, A, Porcu, E, Postmus, I, Pramstaller, PP, Psaty, BM, Ramos, YFM, Rawal, R, Redmond, P, Richards, JB, Rietzschel, ER, Rivadeneira, Fernando, Roef, G, Rotter, JI, Sala, CF, Schlessinger, D, Selvin, E, Slagboom, PE (Eline), Soranzo, N, Sorensen, TIA, Spector, TD, Starr, JM, Stott, DJ, Taes, Y, Taliun, D, Tanaka, T, Thuesen, B, Tiller, D, Toniolo, D, Uitterlinden, André, Visser, Edward, Walsh, JP, Wilson, SG, Wolffenbuttel, BHR, Yang, Q, Zheng, HF, Cappola, A, Peeters, Robin, Naitza, S, Volzke, H, Sanna, S, Kottgen, A, Visser, Theo, and Medici, Marco

Published
2018

14. Pio Monte della Misericordia Church

Author

GAMBARDELLA, Carmine, PISACANE, Nicola, ARGENZIANO, Pasquale, AVELLA, Alessandra, SERRONI G, ABATEGIOVANNI L, MARTIMUCCI D, FIORILLO E., Paolo Giandebiaggi, Andrea Zerbi, Gambardella, Carmine, Pisacane, Nicola, Argenziano, Pasquale, Avella, Alessandra, Serroni, G, Abategiovanni, L, Martimucci, D, and Fiorillo, E.

Published
2014

15. Analyse Socio-Economique et Agrotechnique de la Riziculture de Vallée : le cas de vallées de Samiron et Djimbana

Author

Manzelli M., Seppoloni I., Zucchini E., Bacci M., Fiorillo E., and Tarchiani V.

Subjects
Vallée, Riziculture, Casamance
Abstract

Ce document propose une analyse préliminaire des facteurs qui limitent la riziculture de bas-fond dans les vallées de la Région de Sédhiou pour identifier les mécanismes plus appropriés pour la gestion intégrée et durable des vallées rizicoles. Ce document est constitué de trois composants analysés : (i) socio-économique, (ii) agronomique, (iii) physique et environnementale. Dans le spécifique, ce document analyse deux cas d'étude, la vallée de Djimbana et la vallée de Samiron. Ces deux vallées ont été retenues comme site vitrine par le programme PAPSEN et elles représentent un premier cas d'étude pour affiner les outils qui pourront successivement être appliqués dans les autres vallées de la Région de Sédhiou. Cette analyse se base sur une méthodologie quali-quantitative qui a permis d'aborder les différents aspects et de collecter les informations contenues dans ce document. En particulier, les sources des données et des informations utilisées sont notées ci-dessous: ? les activités de démonstration, d'assistance technique et de suivi agronomique qui ont été réalisées pendant la saison 2014-2015 dans les deux vallées dans le cadre de la collaboration ISRA-CNR; ? des missions de collecte d'information sur le terrain (novembre-décembre 2014); ? les données météo fournies par la Direction Régional pour le Développement Rural ; ? les rencontres avec les institutions étatiques locales et les partenaires du programme PAPSEN; ? la revue bibliographique de la documentation fournie par ces institutions; ? une enquête sur un échantillon de 15 productrices1; ? des focus group réalisés dans 9 villages2 (janvier-février 2015). L'objectif de ce document est de créer une base de connaissances de référence sur laquelle définir les activités de recherche à entreprendre successivement, ainsi que mettre en place un système de suivi et d'évaluation des activités du programme.

Published
2015

16. A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration

Author

Vries, P.S. (Paul) de, Chasman, D.I. (Daniel), Sabater-Lleal, M. (Maria), Chen, M.-H. (Ming-Huei), Huffman, J.E. (Jennifer E.), Steri, M. (Maristella), Tang, W. (Weihong), Teumer, A. (Alexander), Marioni, R.E. (Riccardo), Grossmann, V. (Vera), Hottenga, J.J. (Jouke Jan), Trompet, S. (Stella), Müller-Nurasyid, M. (Martina), Zhao, J.H. (Jing Hua), Brody, J.A. (Jennifer A.), Kleber, M.E. (Marcus), Guo, X. (Xiuqing), Wang, J.J. (Jie Jin), Auer, P. (Paul), Attia, J. (John), Yanek, L.R. (Lisa), Ahluwalia, T.S. (Tarunveer Singh), Lahti, J. (Jari), Venturini, C. (Cristina), Tanaka, T. (Toshiko), Bielak, L.F. (Lawrence F.), Joshi, P.K. (Peter), Rocanin-Arjo, A. (Ares), Kolcic, I. (Ivana), Navarro, P. (Pau), Rose, L.M. (Lynda), Oldmeadow, C. (Christopher), Riess, H. (Helene), Mazur, J. (Johanna), Basu, S. (Saonli), Goel, A. (Anuj), Yang, Q. (Qiong), Ghanbari, M. (Mohsen), Willemsen, G. (Gonneke), Rumley, A. (Ann), Fiorillo, E. (Edoardo), Craen, A.J. (Anton) de, Grotevendt, A. (Anne), Scott, R.A. (Robert), Taylor, K.D. (Kent D.), Delgado, G.E. (Graciela E.), Yao, J. (Jie), Kifley, A. (Annette), Kooperberg, C. (Charles), Qayyum, Q. (Rehan), Lopez, L. (Lornam), Berentzen, T.L. (Tina L.), Räikkönen, K. (Katri), Mangino, M. (Massimo), Bandinelli, S. (Stefania), Peyser, P.A. (Patricia A.), Wild, S. (Sarah), Tregouet, D.-A. (David-Alexandre), Wright, A.F. (Alan), Marten, J. (Jonathan), Zemunik, T. (Tatijana), Morrison, A.C. (Alanna), Sennblad, B. (Bengt), Tofler, G.H. (Geoffrey), Maat, M.P.M. (Moniek) de, Geus, E.J.C. (Eco) de, Lowe, G.D. (Gordon D.), Zoledziewska, M. (Magdalena), Sattar, N. (Naveed), Binder, H. (Harald), Völker, U. (Uwe), Waldenberger, M. (Melanie), Khaw, K.-T. (Kay-Tee), McKnight, B. (Barbara), Huang, J. (Jian), Jenny, N.S. (Nancy), Holliday, E.G. (Elizabeth), Qi, L. (Lihong), Mcevoy, M.G. (Mark G.), Becker, D.M. (Diane), Starr, J.M. (John), Sarin, A.-P., Hysi, P.G. (Pirro), Hernandez, D.G. (Dena), Jhun, M.A. (Min A.), Campbell, H. (Harry), Hamsten, A. (Anders), Sarin, F. (Fernando), McArdle, W.L. (Wendy), Slagboom, P.E. (Eline), Zeller, T. (Tanja), Koenig, W. (Wolfgang), Psaty, B. (Brucem), Haritunians, T. (Talin), Liu, J. (Jingmin), Palotie, A. (Aarno), Uitterlinden, A.G. (André), Stott, D.J. (David J.), Hofman, A. (Albert), Franco, O.H. (Oscar), Polasek, O. (Ozren), Rudan, I. (Igor), Morange, P.-E. (P.), Wilson, J.F. (James F.), Kardia, S.L. (Sharon L.r), Ferrucci, L. (Luigi), Spector, T.D. (Timothy), Eriksson, J.G. (Johan G.), Hansen, T. (Torben), Deary, I.J. (Ian), Becker, L.C. (Lewis), Scott, R.J. (Rodney), Mitchell, P. (Paul), März, W. (Winfried), Wareham, N.J. (Nick J.), Peters, A. (Annette), Greinacher, A. (Andreas), Wild, P.S. (Philipp S.), Jukema, J.W. (Jan Wouter), Boomsma, D.I. (Dorret), Hayward, C. (Caroline), Cucca, F. (Francesco), Tracy, R.P. (Russell), Watkins, H. (Hugh), Reiner, A.P. (Alex P.), Folsom, A.R. (Aaron), Ridker, P.M. (Paul), O'Donnell, C.J. (Christopher J.), Smith, N.L. (Nicholas L.), Strachan, D.P. (David P.), Dehghan, A. (Abbas), Vries, P.S. (Paul) de, Chasman, D.I. (Daniel), Sabater-Lleal, M. (Maria), Chen, M.-H. (Ming-Huei), Huffman, J.E. (Jennifer E.), Steri, M. (Maristella), Tang, W. (Weihong), Teumer, A. (Alexander), Marioni, R.E. (Riccardo), Grossmann, V. (Vera), Hottenga, J.J. (Jouke Jan), Trompet, S. (Stella), Müller-Nurasyid, M. (Martina), Zhao, J.H. (Jing Hua), Brody, J.A. (Jennifer A.), Kleber, M.E. (Marcus), Guo, X. (Xiuqing), Wang, J.J. (Jie Jin), Auer, P. (Paul), Attia, J. (John), Yanek, L.R. (Lisa), Ahluwalia, T.S. (Tarunveer Singh), Lahti, J. (Jari), Venturini, C. (Cristina), Tanaka, T. (Toshiko), Bielak, L.F. (Lawrence F.), Joshi, P.K. (Peter), Rocanin-Arjo, A. (Ares), Kolcic, I. (Ivana), Navarro, P. (Pau), Rose, L.M. (Lynda), Oldmeadow, C. (Christopher), Riess, H. (Helene), Mazur, J. (Johanna), Basu, S. (Saonli), Goel, A. (Anuj), Yang, Q. (Qiong), Ghanbari, M. (Mohsen), Willemsen, G. (Gonneke), Rumley, A. (Ann), Fiorillo, E. (Edoardo), Craen, A.J. (Anton) de, Grotevendt, A. (Anne), Scott, R.A. (Robert), Taylor, K.D. (Kent D.), Delgado, G.E. (Graciela E.), Yao, J. (Jie), Kifley, A. (Annette), Kooperberg, C. (Charles), Qayyum, Q. (Rehan), Lopez, L. (Lornam), Berentzen, T.L. (Tina L.), Räikkönen, K. (Katri), Mangino, M. (Massimo), Bandinelli, S. (Stefania), Peyser, P.A. (Patricia A.), Wild, S. (Sarah), Tregouet, D.-A. (David-Alexandre), Wright, A.F. (Alan), Marten, J. (Jonathan), Zemunik, T. (Tatijana), Morrison, A.C. (Alanna), Sennblad, B. (Bengt), Tofler, G.H. (Geoffrey), Maat, M.P.M. (Moniek) de, Geus, E.J.C. (Eco) de, Lowe, G.D. (Gordon D.), Zoledziewska, M. (Magdalena), Sattar, N. (Naveed), Binder, H. (Harald), Völker, U. (Uwe), Waldenberger, M. (Melanie), Khaw, K.-T. (Kay-Tee), McKnight, B. (Barbara), Huang, J. (Jian), Jenny, N.S. (Nancy), Holliday, E.G. (Elizabeth), Qi, L. (Lihong), Mcevoy, M.G. (Mark G.), Becker, D.M. (Diane), Starr, J.M. (John), Sarin, A.-P., Hysi, P.G. (Pirro), Hernandez, D.G. (Dena), Jhun, M.A. (Min A.), Campbell, H. (Harry), Hamsten, A. (Anders), Sarin, F. (Fernando), McArdle, W.L. (Wendy), Slagboom, P.E. (Eline), Zeller, T. (Tanja), Koenig, W. (Wolfgang), Psaty, B. (Brucem), Haritunians, T. (Talin), Liu, J. (Jingmin), Palotie, A. (Aarno), Uitterlinden, A.G. (André), Stott, D.J. (David J.), Hofman, A. (Albert), Franco, O.H. (Oscar), Polasek, O. (Ozren), Rudan, I. (Igor), Morange, P.-E. (P.), Wilson, J.F. (James F.), Kardia, S.L. (Sharon L.r), Ferrucci, L. (Luigi), Spector, T.D. (Timothy), Eriksson, J.G. (Johan G.), Hansen, T. (Torben), Deary, I.J. (Ian), Becker, L.C. (Lewis), Scott, R.J. (Rodney), Mitchell, P. (Paul), März, W. (Winfried), Wareham, N.J. (Nick J.), Peters, A. (Annette), Greinacher, A. (Andreas), Wild, P.S. (Philipp S.), Jukema, J.W. (Jan Wouter), Boomsma, D.I. (Dorret), Hayward, C. (Caroline), Cucca, F. (Francesco), Tracy, R.P. (Russell), Watkins, H. (Hugh), Reiner, A.P. (Alex P.), Folsom, A.R. (Aaron), Ridker, P.M. (Paul), O'Donnell, C.J. (Christopher J.), Smith, N.L. (Nicholas L.), Strachan, D.P. (David P.), and Dehghan, A. (Abbas)

Abstract

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels.We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ~120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indelswere examined.We identified 41 genome-wide significant fibrinogen loci; of which, 18were newly identified. Therewere no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

Published
2016
Full Text
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18. Population and individual effects of non-coding variants inform genetic risk factors

Author

M., Pala, primary, Zappala, Z., additional, Marongiu, M., additional, Li, X., additional, Davis, J.R., additional, Cusano, R., additional, Crobu, F., additional, Kukurba, K.R., additional, Reiner, F., additional, Berutti, R., additional, Piras, M.G., additional, Mulas, A., additional, Zoledziewska, M., additional, Busonero, F., additional, Maschio, A., additional, Steri, M., additional, Sidore, C., additional, Sanna, S., additional, Fiorillo, E., additional, Battle, A., additional, Novembre, J., additional, Jones, C., additional, Angius, A., additional, Abecasis, G.R., additional, Schlessinger, D., additional, Cucca, F., additional, and Montgomery, S.B., additional

Published
2016
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31. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Author

Polderman, T.J.C., Stefansson, K., Zuccolo, L., Wall, T.L., Stan����kov��, A., Zhan, X., Hunter, D.J., Davila-Velderrain, J., Palviainen, T., Brazel, D.M., 23andMe Research Team, Haller, T., Chen, F., Jiang, Y., Johnson, E.O., Rose, R.J., Martin, N.G., Wedow, R., Rice, J.P., Boehnke, M., Jorgenson, E., Posthuma, D., Haessler, J., Kellis, M., Young, K.A., Jansen, P.R., Bjornsdottir, G., Kardia, S.L.R., Metspalu, A., Chen, C., Eaton, C.B., Madden, P.A.F., Gillespie, N.A., McGue, M., Choquet, H., McMahon, G., Jang, S.-K., Faul, J.D., Nielsen, J.B., Fritsche, L.G., Yin, J., Cucca, F., Medland, S.E., Vrieze, S., Thorgeirsson, T.E., Loukola, A., Reginsson, G.W., Tian, C., Orr��, V., HUNT All-In Psychiatry, Iacono, W.G., Gordon, S.D., Kraft, P., Fiorillo, E., Reiner, A.P., Willer, C.J., Boomsma, D.I., Munaf��, M.R., Tyrfingsson, T., Kaprio, J., Laakso, M., Zajac, G.J.M., Willemsen, G., Hickie, I.B., Runarsdottir, V., Li, Y., Hottenga, J.-J., McQueen, M.B., Ehringer, M.A., Zhou, W., Smith, J.A., Taylor, A.E., Tindle, H.A., Kooperberg, C., Boardman, J.D., Lee, J.J., McGuire, D., Zhao, W., Mulas, A., Cornelis, M.C., Lind, P.A., Hveem, K., Weisner, C., Datta, G., Gudbjartsson, D.F., Lutz, S.M., M��gi, R., Hewitt, J.K., Turman, C., Thai, K.K., Stallings, M.C., Kamatani, Y., Hopfer, C.J., David, S.P., Young, H., Rimm, E., Bierut, L.J., Ling, Y., Foerster, J.R., Harris, K.M., Davies, G.E., Krauter, K.S., Matoba, N., Abecasis, G., Esko, T., Keller, M.C., Whitfield, J.B., Liu, D.J., Huang, H., Stitzel, J.A., Liu, M., Peters, U., Saccone, N.L., Docherty, A.R., Pandit, A., Stefansson, H., Hokanson, J.E., Heath, A.C., Okada, Y., Weir, D.R., and Mohlke, K.L.

Subjects
3. Good health
Abstract

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders. They are heritable and etiologically related behaviors that have been resistant to gene discovery efforts. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.

33. Overexpression of the Cytokine BAFF and Autoimmunity Risk

Author

Steri, M, Orrù, V, Idda, ML, Pitzalis, M, Pala, M, Zara, I, Sidore, C, Faà, V, Floris, M, Deiana, M, Asunis, I, Porcu, E, Mulas, A, Piras, MG, Lobina, M, Lai, S, Marongiu, M, Serra, V, Sole, G, Busonero, F, Maschio, A, Cusano, R, Cuccuru, G, Deidda, F, Poddie, F, Farina, G, Dei, M, Virdis, F, Olla, S, Satta, MA, Pani, M, Delitala, A, Cocco, E, Frau, J, Coghe, G, Lorefice, L, Fenu, G, Ferrigno, P, Ban, M, Barizzone, N, Leone, M, Guerini, FR, Piga, M, Firinu, D, Kockum, I, Lima Bomfim, I, Olsson, T, Alfredsson, L, Suarez, A, Carreira, PE, Castillo-Palma, MJ, Marcus, JH, Congia, M, Angius, A, Melis, M, Gonzalez, A, Alarcón Riquelme, ME, Da Silva, BM, Marchini, M, Danieli, MG, Del Giacco, S, Mathieu, A, Pani, A, Montgomery, SB, Rosati, G, Hillert, J, Sawcer, S, D'Alfonso, S, Todd, JA, Novembre, J, Abecasis, GR, Whalen, MB, Marrosu, MG, Meloni, A, Sanna, S, Gorospe, M, Schlessinger, D, Fiorillo, E, Zoledziewska, M, and Cucca, F

Subjects
transcription, genetic, phenotype, case-control studies, gene Expression, autoimmunity, polymorphism, single nucleotide, multiple sclerosis, sequence analysis, RNA, 3. Good health, MicroRNAs, INDEL Mutation, Italy, B-Cell Activating Factor, Lupus Erythematosus, Systemic, humans, Genome-Wide Association Study, risk
Abstract

$\textbf{BACKGROUND}$: Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. $\textbf{METHODS}$: Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. $\textbf{RESULTS}$: A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. $\textbf{CONCLUSIONS}$: A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).

34. A WebGIS application for precision viticulture: From research to operative practices

Author

Filippis, T., Rocchi, L., Fiorillo, E., and Lorenzo Genesio

Subjects
Open Source, Geodatabase, Viticulture, Geoportal, WebGIS
Abstract

Demands for geospatial information and geodata accessibility to support vineyard management using new technology for precision farming are increasing worldwide. In this paper a WebGIS application is presented, it has been developed to support the on-going researches of Consorzio Tuscania Project on precision viticulture in Tuscany, aiming at the assessment of the impact of different vineyard canopy management techniques on grape quality. Within this framework, a parallel goal was also to build a Web service to support operational applications for agronomic treatments and grape harvest and to provide digital images for mobile devices that can be also integrated on agricultural machineries. A geoportal has been developed to organize geospatial data and services through (i) a viewer, (ii) a catalogue containing metadata records and (iii) a geodatabase where all data and results of Research Project are stored. Thanks to web services, users can view, analyse and download vegetation indices derived from airborne remote sensing high-resolution products, agrometeorological data of a Wireless Sensor Network located in the vineyards and others reference data to support vineyard precision farming practices. The web architecture as well as the user interface were implemented using open source tools in order to guarantee the web application sustainability and the implementation of customized geospatial functions required by the project stakeholders. MapServer was used with PHP/Ajax technologies to develop all components of Web mapping application and PostgreSQL was used as data warehouse for geodata and alphanumeric data management. On-the-fly processing and map visualization show the high potentialities in a reliable, accessible and personalized use of Internet to monitor the vineyards characteristics during the growing season and to improve grape harvest management.

37. The power of genetic diversity in genome-wide association studies of lipids

Author

Graham, Sarah E, Clarke, Shoa L, Wu, Kuan-Han H, Kanoni, Stavroula, Zajac, Greg JM, Ramdas, Shweta, Surakka, Ida, Ntalla, Ioanna, Vedantam, Sailaja, Winkler, Thomas W, Locke, Adam E, Marouli, Eirini, Hwang, Mi Yeong, Han, Sohee, Narita, Akira, Choudhury, Ananyo, Bentley, Amy R, Ekoru, Kenneth, Verma, Anurag, Trivedi, Bhavi, Martin, Hilary C, Hunt, Karen A, Hui, Qin, Klarin, Derek, Zhu, Xiang, Thorleifsson, Gudmar, Helgadottir, Anna, Gudbjartsson, Daniel F, Holm, Hilma, Olafsson, Isleifur, Akiyama, Masato, Sakaue, Saori, Terao, Chikashi, Kanai, Masahiro, Zhou, Wei, Brumpton, Ben M, Rasheed, Humaira, Ruotsalainen, Sanni E, Havulinna, Aki S, Veturi, Yogasudha, Feng, QiPing, Rosenthal, Elisabeth A, Lingren, Todd, Pacheco, Jennifer Allen, Pendergrass, Sarah A, Haessler, Jeffrey, Giulianini, Franco, Bradford, Yuki, Miller, Jason E, Campbell, Archie, Lin, Kuang, Millwood, Iona Y, Hindy, George, Rasheed, Asif, Faul, Jessica D, Zhao, Wei, Weir, David R, Turman, Constance, Huang, Hongyan, Graff, Mariaelisa, Mahajan, Anubha, Brown, Michael R, Zhang, Weihua, Yu, Ketian, Schmidt, Ellen M, Pandit, Anita, Gustafsson, Stefan, Yin, Xianyong, Luan, Jian’an, Zhao, Jing-Hua, Matsuda, Fumihiko, Jang, Hye-Mi, Yoon, Kyungheon, Medina-Gomez, Carolina, Pitsillides, Achilleas, Hottenga, Jouke Jan, Willemsen, Gonneke, Wood, Andrew R, Ji, Yingji, Gao, Zishan, Haworth, Simon, Mitchell, Ruth E, Chai, Jin Fang, Aadahl, Mette, Yao, Jie, Manichaikul, Ani, Warren, Helen R, Ramirez, Julia, Bork-Jensen, Jette, Kårhus, Line L, Goel, Anuj, Sabater-Lleal, Maria, Noordam, Raymond, Sidore, Carlo, Fiorillo, Edoardo, McDaid, Aaron F, Marques-Vidal, Pedro, Wielscher, Matthias, Trompet, Stella, Sattar, Naveed, Møllehave, Line T, Thuesen, Betina H, Munz, Matthias, Zeng, Lingyao, Huang, Jianfeng, Yang, Bin, Poveda, Alaitz, Kurbasic, Azra, Lamina, Claudia, Forer, Lukas, Scholz, Markus, Galesloot, Tessel E., Bradfield, Jonathan P., Daw, E Warwick, Zmuda, Joseph M, Mitchell, Jonathan S, Fuchsberger, Christian, Christensen, Henry, Brody, Jennifer A, Feitosa, Mary F, Wojczynski, Mary K, Preuss, Michael, Mangino, Massimo, Christofidou, Paraskevi, Verweij, Niek, Benjamins, Jan W, Engmann, Jorgen, Kember, Rachel L, Slieker, Roderick C, Lo, Ken Sin, Zilhao, Nuno R, Le, Phuong, Kleber, Marcus E, Delgado, Graciela E, Huo, Shaofeng, Ikeda, Daisuke D, Iha, Hiroyuki, Yang, Jian, Liu, Jun, Leonard, Hampton L, Marten, Jonathan, Schmidt, Börge, Arendt, Marina, Smyth, Laura J, Cañadas-Garre, Marisa, Wang, Chaolong, Nakatochi, Masahiro, Wong, Andrew, Hutri-Kähönen, Nina, Sim, Xueling, Xia, Rui, Huerta-Chagoya, Alicia, Fernandez-Lopez, Juan Carlos, Lyssenko, Valeriya, Ahmed, Meraj, Jackson, Anne U, Irvin, Marguerite R, Oldmeadow, Christopher, Kim, Han-Na, Ryu, Seungho, Timmers, Paul RHJ, Arbeeva, Liubov, Dorajoo, Rajkumar, Lange, Leslie A, Chai, Xiaoran, Prasad, Gauri, Lorés-Motta, Laura, Pauper, Marc, Long, Jirong, Li, Xiaohui, Theusch, Elizabeth, Takeuchi, Fumihiko, Spracklen, Cassandra N, Loukola, Anu, Bollepalli, Sailalitha, Warner, Sophie C, Wang, Ya Xing, Wei, Wen B., Nutile, Teresa, Ruggiero, Daniela, Sung, Yun Ju, Hung, Yi-Jen, Chen, Shufeng, Liu, Fangchao, Yang, Jingyun, Kentistou, Katherine A, Gorski, Mathias, Brumat, Marco, Meidtner, Karina, Bielak, Lawrence F, Smith, Jennifer A, Hebbar, Prashantha, Farmaki, Aliki-Eleni, Hofer, Edith, Lin, Maoxuan, Xue, Chao, Zhang, Jifeng, Concas, Maria Pina, Vaccargiu, Simona, van der Most, Peter J, Pitkänen, Niina, Cade, Brian E, Lee, Jiwon, van der Laan, Sander W., Chitrala, Kumaraswamy Naidu, Weiss, Stefan, Zimmermann, Martina E, Lee, Jong Young, Choi, Hyeok Sun, Nethander, Maria, Freitag-Wolf, Sandra, Southam, Lorraine, Rayner, Nigel W, Wang, Carol A, Lin, Shih-Yi, Wang, Jun-Sing, Couture, Christian, Lyytikäinen, Leo-Pekka, Nikus, Kjell, Cuellar-Partida, Gabriel, Vestergaard, Henrik, Hildalgo, Bertha, Giannakopoulou, Olga, Cai, Qiuyin, Obura, Morgan O, van Setten, Jessica, Li, Xiaoyin, Schwander, Karen, Terzikhan, Natalie, Shin, Jae Hun, Jackson, Rebecca D, Reiner, Alexander P, Martin, Lisa Warsinger, Chen, Zhengming, Li, Liming, Highland, Heather M, Young, Kristin L, Kawaguchi, Takahisa, Thiery, Joachim, Bis, Joshua C, Nadkarni, Girish N., Launer, Lenore J, Li, Huaixing, Nalls, Mike A, Raitakari, Olli T, Ichihara, Sahoko, Wild, Sarah H, Nelson, Christopher P, Campbell, Harry, Jäger, Susanne, Nabika, Toru, Al-Mulla, Fahd, Niinikoski, Harri, Braund, Peter S, Kolcic, Ivana, Kovacs, Peter, Giardoglou, Tota, Katsuya, Tomohiro, Bhatti, Konain Fatima, de Kleijn, Dominique, de Borst, Gert J., Kim, Eung Kweon, Adams, Hieab H.H., Ikram, M. Arfan, Zhu, Xiaofeng, Asselbergs, Folkert W, Kraaijeveld, Adriaan O, Beulens, Joline WJ, Shu, Xiao-Ou, Rallidis, Loukianos S, Pedersen, Oluf, Hansen, Torben, Mitchell, Paul, Hewitt, Alex W, Kähönen, Mika, Pérusse, Louis, Bouchard, Claude, Tönjes, Anke, Chen, Yii-Der Ida, Pennell, Craig E, Mori, Trevor A, Lieb, Wolfgang, Franke, Andre, Ohlsson, Claes, Mellström, Dan, Cho, Yoon Shin, Lee, Hyejin, Yuan, Jian-Min, Koh, Woon-Puay, Rhee, Sang Youl, Woo, Jeong-Taek, Heid, Iris M, Stark, Klaus J, Völzke, Henry, Homuth, Georg, Evans, Michele K, Zonderman, Alan B, Polasek, Ozren, Pasterkamp, Gerard, Hoefer, Imo E, Redline, Susan, Pahkala, Katja, Oldehinkel, Albertine J, Snieder, Harold, Biino, Ginevra, Schmidt, Reinhold, Schmidt, Helena, Chen, Y Eugene, Bandinelli, Stefania, Dedoussis, George, Thanaraj, Thangavel Alphonse, Kardia, Sharon LR, Kato, Norihiro, Schulze, Matthias B, Girotto, Giorgia, Jung, Bettina, Böger, Carsten A, Joshi, Peter K, Bennett, David A, De Jager, Philip L, Lu, Xiangfeng, Mamakou, Vasiliki, Brown, Morris, Caulfield, Mark J, Munroe, Patricia B, Guo, Xiuqing, Ciullo, Marina, Jonas, Jost B., Samani, Nilesh J, Chasman, Daniel I., Kaprio, Jaakko, Pajukanta, Päivi, Tusié-Luna, Teresa, Aguilar-Salinas, Carlos A, Adair, Linda S, Bechayda, Sonny Augustin, de Silva, H. 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M., Ramdas, S., Surakka, I., Ntalla, I., Vedantam, S., Winkler, T. W., Locke, A. E., Marouli, E., Hwang, M. Y., Han, S., Narita, A., Choudhury, A., Bentley, A. R., Ekoru, K., Verma, A., Trivedi, B., Martin, H. C., Hunt, K. A., Hui, Q., Klarin, D., Zhu, X., Thorleifsson, G., Helgadottir, A., Gudbjartsson, D. F., Holm, H., Olafsson, I., Akiyama, M., Sakaue, S., Terao, C., Kanai, M., Zhou, W., Brumpton, B. M., Rasheed, H., Ruotsalainen, S. E., Havulinna, A. S., Veturi, Y., Feng, Q. P., Rosenthal, E. A., Lingren, T., Pacheco, J. A., Pendergrass, S. A., Haessler, J., Giulianini, F., Bradford, Y., Miller, J. E., Campbell, A., Lin, K., Millwood, I. Y., Hindy, G., Rasheed, A., Faul, J. D., Zhao, W., Weir, D. R., Turman, C., Huang, H., Graff, M., Mahajan, A., Brown, M. R., Zhang, W., Yu, K., Schmidt, E. M., Pandit, A., Gustafsson, S., Yin, X., Luan, J., Zhao, J. -H., Matsuda, F., Jang, H. -M., Yoon, K., Medina-Gomez, C., Pitsillides, A., Hottenga, J. J., Willemsen, G., Wood, A. 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D., Jousilahti, P., Salomaa, V., Hveem, K., Asvold, B. O., Kubo, M., Kamatani, Y., Okada, Y., Murakami, Y., Thorsteinsdottir, U., Stefansson, K., Ho, Y. -L., Lynch, J. A., Rader, D. J., Tsao, P. S., Chang, K. -M., Cho, K., O'Donnell, C. J., Gaziano, J. M., Wilson, P., Rotimi, C. N., Hazelhurst, S., Ramsay, M., Trembath, R. C., van Heel, D. A., Tamiya, G., Yamamoto, M., Kim, B. -J., Mohlke, K. L., Frayling, T. M., Hirschhorn, J. N., Kathiresan, S., Boehnke, M., Natarajan, P., Peloso, G. M., Brown, C. D., Morris, A. P., Assimes, T. L., Deloukas, P., Sun, Y. V., Willer, C. J., Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, APH - Methodology, AMS - Ageing & Vitality, and AMS - Sports

Subjects
blood lipid level, Multifactorial Inheritance, GWAS, blood lipid levels, cardiovascular disease, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Medizin, LOCI, ANCESTRY, VARIANTS, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Article, Population Groups, SDG 3 - Good Health and Well-being, Humans, Genetic Predisposition to Disease, METAANALYSIS, POLYMORPHISMS, RISK, Multidisciplinary, Cardiovascular Diseases, Genome-Wide Association Study, Cardiovascular Diseases/genetics, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study/methods, Polymorphism, Single Nucleotide/genetics, CHOLESTEROL, Human Genetics, INDIVIDUALS, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], DISCOVERY, LOW-FREQUENCY, Delivery of Health Care
Abstract

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use 1 . Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels 2 , heart disease remains the leading cause of death worldwide 3 . Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS 4-23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns 24 . Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine 25 , we anticipate that increased diversity of participants will lead to more accurate and equitable 26 application of polygenic scores in clinical practice.

Published
2021

38. Role of connexin-43 hemichannels in the pathogenesis of Yersinia enterocolitica.

Author

Almonacid, L. A. Velasquez, Tafuri, S., Dipineto, L., Matteoli, G., Fiorillo, E., Morte, R. Della, Fioretti, A., Menna, L. F., and Staiano, N.

Subjects
*CONNEXINS, *YERSINIA, *TYROSINE, *PHOSPHORYLATION, *BACTERIA
Abstract

Connexin (Cx) channels are sites of cytoplasmic communication between contacting cells. Evidence indicates that the opening of hemichannels occurs under both physiological and pathological conditions. In this paper, the involvement of Cx-43 hemichannels is demonstrated in the pathogenesis of Yersinia. Parental HeLa cells and transfected HeLa cells stably expressing Cx-43 (HCx43) were infected with Yersinia enterocolitica, and bacterial uptake was measured by the colony-forming unit method. Bacterial uptake was higher in HCx43 cells than in parental cells and was inhibited by the Cx channel blocker, 18-α-glycyrrhetinic acid (AGA). The inhibitory effect of AGA was more pronounced on the Y. enterocolitica uptake by HCx43 cells than by parental cells. The ability of HCx43 cells to incorporate the permeable fluorescent tracer Lucifer Yellow (LY) was assessed. Dye incorporation was inhibited by AGA, whereas Y. enterocolitica infection of HCx43 cells increased LY incorporation. Western blotting analysis demonstrated that Y. enterocolitica infection of HCx43 cells induced tyrosine phosphorylation of Cx-43, thus supporting a critical role for Cx-43 in the strategies exploited by bacterial pathogens to invade nonphagocytic cells. [ABSTRACT FROM AUTHOR]

Published
2009
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39. The fundamental issues of the scientific method for attribution: a reassessment through case studies

Author

F. Fiorillo, C. Matteucci, G. Garcia, F. Castagna, A. E. Scorcu, L. Vici, R. Zanola, J. Butterwick, M. Cecilia, R. Cecilia, A. C. Fariselli, F. Condello, R. savigni, M. den Leeuw, C. Matteucci, F. Fiorillo,E. Gnignera, F. Petrucci, P. Cotte, B. Mora-Serrano, G. Garcia, M. Vandini, C. Matteucci, and F. Fiorillo, C. Matteucci

Subjects
Fakes, forgeries, technical art history
Abstract

The single volume is the aftermath of the international conference held at the Cultural Heritage Department of the University of Bologna. It is aimed at analyzing the problem of fake heritage through an interdisciplinary approach, wich shows both its entirety in the modern society and its presence in the human history not onli limited to the art object themselves but to the Cultural Heritage in its broad meaning.

Published
2018

40. L'apprendistato

Author

LASSANDARI, ANDREA, Luigi Fiorillo e Adalberto Perulli, and Lassandari Andrea

Subjects
Lavoro Rapporto Forme contrattuali Apprendistato
Abstract

Viene analizzata la disciplina vigente del contratto di apprendistato, come modificata ai sensi del d. lgs. n 81 del 2015.

Published
2015

41. Il lavoro intermittente

Author

VINCIERI, MARTINA, diretto da Luigi Fiorillo e Adalberto Perulli, and Vincieri, Martina

Subjects
LAVORO INTERMITTENTE, DISCONTINUITÀ
Abstract

Il saggio prende in esame l'’iter normativo del lavoro intermittente, tipologia caratterizzata da notevole flessibilità. L'attenzione è, in particolare, rivolta all'inquadramento giuridico, alla fattispecie priva del vincolo di risposta in capo al prestatore di lavoro, nonché alla disciplina del rapporto.

Published
2014

42. Le modifiche al lavoro intermittente

Author

VINCIERI, MARTINA, diretto da Luigi Fiorillo e Adalberto Perulli, and Vincieri, Martina

Subjects
MODIFICHE, obbligo di comunicazione, lavoro inermittente
Abstract

L.A. si sofferma sulle recenti modifiche introddotte alla fattispecie del lavoro intermittente dalla l. n. 92/2012, nonchè dalla l. n. 99/2013. In particolare sono presi in considerazione i residui casi di ricorso al contratto, le ipotesi soggettive ed il nuovo obbligo di comunicazione a carico del datore di lavoro.

Published
2014

43. Comunità civile, patria, nazione: una costellazione semantica nel pensiero di Antonio Rosmini

Author

LIMONE, Giuseppe, G LIMONE, Vanda Fiorillo e Gianluca Dioni, and Limone, Giuseppe

Subjects
ROSMINI, NAZIONE, COMUNITA' CIVILE
Abstract

Il saggio cerca di ricostruire in modo nuovo le coordinate del pensiero rosminiano, ponendo in rapporto le questioni della persona, della società della comunità civile, della nazione e dello stato. Si perviene all’identificazione, in Rosmini, di un pensiero, tutto da ricostruire, sulla identità della comunità civile all’interno di un percorso critico che scandisce le tappe della vita della nazione come formazione storicamente determinata

Published
2013

44. Role of the serotonin transporter in heart valve development and disease

Author

Anna Spina, Luigi Michele Pavone, E. Fiorillo, Luigi Avallone, Vincenzo Mastellone, R. Lo Muto, Pavone, LUIGI MICHELE, Spina, A., Mastellone, Vincenzo, Lo Muto, R., Fiorillo, E., and Avallone, Luigi

Subjects
Serotonin Plasma Membrane Transport Proteins, medicine.medical_specialty, General Veterinary, biology, business.industry, Heart Valve Diseases, General Medicine, Disease, Heart Valves, Mice, medicine.anatomical_structure, Endocrinology, Gene Expression Regulation, Internal medicine, biology.protein, Medicine, Animals, Heart valve, business, Serotonin transporter
Published
2009

45. Expression of orexin A and its receptor 1 in the rat epididymis

Author

Matilde Basile, Luigi Michele Pavone, Enrica Fiorillo, Luigi Avallone, Norma Staiano, Alfredo Vittoria, Roberta Lo Muto, E. Langella, Simona Tafuri, Tafuri, Simona, Pavone, LUIGI MICHELE, Lo Muto, R., Basile, M., Langella, E., Fiorillo, E., Avallone, Luigi, Staiano, Norma, and Vittoria, Alfredo

Subjects
Male, Receptors, Neuropeptide, medicine.medical_specialty, Physiology, Clinical Biochemistry, Blotting, Western, Biology, Biochemistry, Receptors, G-Protein-Coupled, Cellular and Molecular Neuroscience, Orexin-A, Endocrinology, Orexin Receptors, Internal medicine, mental disorders, medicine, Animals, Rats, Wistar, Receptor, Epididymis, Messenger RNA, Orexins, Reverse Transcriptase Polymerase Chain Reaction, Neuropeptides, Intracellular Signaling Peptides and Proteins, Molecular biology, Immunohistochemistry, Orexin receptor, Orexin, Rats, Blot, medicine.anatomical_structure, Gene Expression Regulation, Cytoplasm, hormones, hormone substitutes, and hormone antagonists
Abstract

The hypothalamic peptide orexin A (oxA) derives from the proteolytic cleavage of the precursor molecule prepro-orexin. It binds with the high affinity G-protein-coupled orexin receptor 1 (OX1R). Here, we report the detection of oxA and OX1R in the principal cells of the rat caudal epididymis by immunohistochemistry. Both oxA and OX1R immunolabelling showed cytoplasmic supranuclear localization, filling the apical portion of the cells. The expression of prepro-orexin and OX1R mRNA transcripts in the rat epididymis was assessed by reverse-transcriptase polymerase chain reaction, while the presence of both these proteins in the tissue was confirmed by Western blotting analysis. Our findings provide the evidence for the presence of oxA and OX1R in the rat epididymis, and demonstrate that both proteins are locally synthesised, thus suggesting a role for oxA in governing the fertilizing capability of the immature male gamete.

Published
2009

47. Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles.

Author

Huffman JE, Nicholas J, Hahn J, Heath AS, Raffield LM, Yanek LR, Brody JA, Thibord F, Almasy L, Bartz TM, Bielak LF, Bowler RP, Carrasquilla GD, Chasman DI, Chen MH, Emmert DB, Ghanbari M, Haessler J, Hottenga JJ, Kleber ME, Le NQ, Lee J, Lewis JP, Li-Gao R, Luan J, Malmberg AL, Mangino M, Marioni R, Martinez-Perez A, Pankratz N, Polasek O, Richmond A, Rodriguez BAT, Rotter JI, Steri M, Suchon P, Trompet S, Weiss S, Zare M, Auer PL, Cho M, Christofidou P, Davies G, de Geus EJ, Deleuze JF, Delgado GE, Ekunwe L, Faraday N, Gogele M, Greinacher A, Gao H, Howard TE, Joshi PK, Kilpeläinen TO, Lahti J, Linneberg A, Naitza S, Noordam R, Vergés FP, Rich SS, Rosendaal FR, Rudan I, Ryan KA, Souto JCC, van Rooij FJA, Wang H, Zhao W, Becker L, Beswick A, Brown MR, Cade B, Campbell H, Cho K, Crapo J, Curran J, de Maat MPM, Doyle MF, Elliott P, Floyd JS, Fuchsberger C, Grarup N, Guo X, Harris S, Hou L, Kolcic I, Kooperberg C, Menni C, Nauck M, O'Connell JR, Orru V, Psaty BM, Räikkönen K, Smith JA, Soria JM, Stott D, van Hylckama Vlieg A, Watkins H, Willemsen G, Wilson PW, Ben-Shlomo Y, Blangero J, Boomsma D, Cox SR, Dehghan A, Eriksson JG, Fiorillo E, Fornage M, Hansen T, Hayward C, Ikram MA, Jukema JW, Kardia S, Lange L, Maerz W, Mathias R, Mitchell BD, Mook-Kanamori DO, Morange PE, Pedersen O, Pramstaller PP, Redline S, Reiner AP, Ridker PM, Silverman EK, Spector TD, Volker U, Wareham N, Wilson J, Yao J, Tregouet DA, Johnson AD, Wolberg AS, de Vries PS, Sabater-Lleal M, Morrison A, and Smith NL

Abstract

Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI's Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10 percentage points higher in African populations. Three signals (SERPINA1, ZFP36L2, and TLR10) contain predicted deleterious missense variants. Two loci, SOCS3 and HPN, each harbor two conditionally distinct, non-coding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common in African ancestry populations but extremely rare in Europeans (MAFAFR=0.180; MAFEUR=0.008). Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation., (Copyright © 2024 American Society of Hematology.)

Published
2024
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48. Vascular density normative data of radial peripapillary capillary plexus in healthy Caucasian subjects.

Author

Serra R, Pinna A, Angius A, Rallo V, Marongiu M, Launer L, Gorospe M, Schlessinger D, Coscas F, Fiorillo E, and Cucca F

Abstract

Purpose: To establish a normative database for vascular density (VD) of radial peripapillary capillary plexus (RPC) in healthy Caucasian subjects., Methods: 633 healthy Caucasian subjects underwent a complete ophthalmological examination, including slit-lamp biomicroscopy, best corrected visual acuity measurement with Early Treatment Diabetic Retinopathy Study charts, intraocular pressure measurement, fundus examination, and macular and optic nerve head (ONH) structural optical coherence tomography (OCT). En-face 4.5 × 4.5 mm OCT angiography scans of the RPC plexus were recorded and VD values, automatically provided by the AngioAnalytics™ software, noted. We statistically estimated the impact of age and gender on RPC VD values using a linear mixed model., Results: 560 subjects fully met inclusion criteria and, according to age, were stratified into 5 groups: 18-50 years (77), 51-60 years (160), 61-70 years (110), 71-80 years (132), and ≥ 81 years (81). Overall, mean RPC VD of the whole en-face image was 53.03 ± 4.27%. Age was significantly related to RPC VD values of whole en-face image (r = -0.454; p < 0.0001), which decreased with aging. The linear mixed model disclosed that age has a statistically significant effect on RPC VD values in whole en-face image (p = 0.0006). As age increases, RPC VD values decrease by 0.12 per year. Conversely, no significant gender-related differences were found in terms of RPC VD values of whole en-face image and each parapapillary quadrant analyzing all age group., Conclusions: Results show that RPC VD values in healthy Caucasian subjects decrease with aging. These data may be used to create a reference normative database useful for clinical use., Key Messages: What is known Radial peripapillary capillary (RPC) plexus, consisting of long parallel capillaries with rare bifurcations and anastomosis and extending straight along the course of the retinal nerve fiber layer to the posterior pole, may be affected early in some optic nerve head (ONH) and retinal diseases. What is new This study reports RPC vascular density (VD) values, automatically measured on optical coherence tomography angiography, in healthy Caucasian subjects, demonstrating that age is negatively related to RPC VD values. Results show that RPC VD values in healthy Caucasian subjects decrease with aging. These data may be used to create a reference normative database useful for clinical use., (© 2024. The Author(s).)

Published
2024
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49. Intestinal Blastocystis is linked to healthier diets and more favorable cardiometabolic outcomes in 56,989 individuals from 32 countries.

Author

Piperni E, Nguyen LH, Manghi P, Kim H, Pasolli E, Andreu-Sánchez S, Arrè A, Bermingham KM, Blanco-Míguez A, Manara S, Valles-Colomer M, Bakker E, Busonero F, Davies R, Fiorillo E, Giordano F, Hadjigeorgiou G, Leeming ER, Lobina M, Masala M, Maschio A, McIver LJ, Pala M, Pitzalis M, Wolf J, Fu J, Zhernakova A, Cacciò SM, Cucca F, Berry SE, Ercolini D, Chan AT, Huttenhower C, Spector TD, Segata N, and Asnicar F

Subjects
Humans, Male, Female, Blastocystis Infections, Adult, Middle Aged, Intestines parasitology, Intestines microbiology, Cardiovascular Diseases prevention & control, Metagenome, Blastocystis metabolism, Gastrointestinal Microbiome, Diet, Obesity
Abstract

Diet impacts human health, influencing body adiposity and the risk of developing cardiometabolic diseases. The gut microbiome is a key player in the diet-health axis, but while its bacterial fraction is widely studied, the role of micro-eukaryotes, including Blastocystis, is underexplored. We performed a global-scale analysis on 56,989 metagenomes and showed that human Blastocystis exhibits distinct prevalence patterns linked to geography, lifestyle, and dietary habits. Blastocystis presence defined a specific bacterial signature and was positively associated with more favorable cardiometabolic profiles and negatively with obesity (p < 1e-16) and disorders linked to altered gut ecology (p < 1e-8). In a diet intervention study involving 1,124 individuals, improvements in dietary quality were linked to weight loss and increases in Blastocystis prevalence (p = 0.003) and abundance (p < 1e-7). Our findings suggest a potentially beneficial role for Blastocystis, which may help explain personalized host responses to diet and downstream disease etiopathogenesis., Competing Interests: Declaration of interests G.H., J.W., and T.D.S. are co-founders of ZOE Ltd. G.H., J.W., R.D., F.G., K.M.B., A.A., and E.R.L. are or have been employees of Zoe Ltd. N.S., F.A., S.E.B., and T.D.S. are consultants to ZOE Ltd. T.D.S., R.D., J.W., G.H., N.S., and S.E.B. receive options with ZOE Ltd. All other authors declare no competing interests. Zoe Ltd. holds the following patent applications on Blastocystis: US patent pending application 17/203,678; Europe patent pending application 21713392.5 and 24386003.8; and PCT (World) patent pending application PCT/EP2022/076241., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2024
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50. A large-scale screening identified in USH2A gene the P3272L founder pathogenic variant explaining familial Usher syndrome in Sardinia, Italy.

Author

Serra R, Rallo V, Steri M, Olla S, Piras MG, Marongiu M, Gorospe M, Schlessinger D, Pinna A, Fiorillo E, Cucca F, and Angius A

Subjects
Humans, Italy epidemiology, Male, Female, Adult, Middle Aged, Extracellular Matrix Proteins genetics, DNA Mutational Analysis, Tomography, Optical Coherence, Phenotype, Founder Effect, Mutation, Missense, Electroretinography, Young Adult, Adolescent, Visual Acuity, Genetic Testing methods, Usher Syndromes genetics, Usher Syndromes diagnosis, Pedigree
Abstract

Background: Usher syndrome (USH) encompasses a group of disorders characterized by congenital sensorineural hearing loss (SNHL) and retinitis pigmentosa (RP). We described the clinical findings, natural history, and molecular analyses of USH patients identified during a large-scale screening to identify quantitative traits related to ocular disorders in the SardiNIA project cohort., Methods: We identified 3 USH-affected families out of a cohort of 6,148 healthy subjects. 9 subjects presented a pathological phenotype, with SNHL and RP. All patients and their family members underwent a complete ophthalmic examination including best-corrected visual acuity, slit-lamp biomicroscopy, fundoscopy, fundus autofluorescence, spectral-domain optical coherence tomography, and electrophysiological testing. Audiological evaluation was performed with a clinical audiometer. Genotyping was performed using several arrays integrated with whole genome sequence data providing approximately 22 million markers equally distributed for each subject analyzed. Molecular diagnostics focused on analysis of the following candidate genes: MYO7A, USH1C, CDH23, PCDH15, USH1G, CIB2, USH2A, GPR98, DFNB31, CLRN1, and PDZD7., Results: A single missense causal variant in USH2A gene was identified in homozygous status in all patients and in heterozygous status in unaffected parents. The presence of multiple homozygous patients with the same phenotypic severity of the syndromic form suggests that the Sardinian USH phenotype is the result of a founder effect on a specific pathogenic variant related haplotype. The frequency of heterozygotes in general Sardinian population is 1.89. Additionally, to provide new insights into the structure of usherin and the pathological mechanisms caused by small pathogenic in-frame variants, like p.Pro3272Leu, molecular dynamics simulations of native and mutant protein-protein and protein-ligand complexes were performed that predicted a destabilization of the protein with a decrease in the free energy change., Conclusions: Our results suggest that our approach is effective for the genetic diagnosis of USH. Based on the heterozygous frequency, targeted screening of this variant in the general population and in families at risk or with familial USH can be suggested. This can lead to more accurate molecular diagnosis, better genetic counseling, and improved molecular epidemiology data that are critical for future intervention plans., Trial Registration: We did not perform any health-related interventions for the participants., (© 2024. The Author(s).)

Published
2024
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