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Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2020-02-27 , DOI: 10.1016/j.ajhg.2020.02.006 Chen Li 1 , Svetlana Stoma 2 , Luca A Lotta 3 , Sophie Warner 4 , Eva Albrecht 5 , Alessandra Allione 6 , Pascal P Arp 7 , Linda Broer 7 , Jessica L Buxton 8 , Alexessander Da Silva Couto Alves 9 , Joris Deelen 10 , Iryna O Fedko 11 , Scott D Gordon 12 , Tao Jiang 13 , Robert Karlsson 14 , Nicola Kerrison 3 , Taylor K Loe 15 , Massimo Mangino 16 , Yuri Milaneschi 17 , Benjamin Miraglio 18 , Natalia Pervjakova 19 , Alessia Russo 6 , Ida Surakka 20 , Ashley van der Spek 21 , Josine E Verhoeven 17 , Najaf Amin 21 , Marian Beekman 22 , Alexandra I Blakemore 23 , Federico Canzian 24 , Stephen E Hamby 2 , Jouke-Jan Hottenga 11 , Peter D Jones 4 , Pekka Jousilahti 25 , Reedik Mägi 19 , Sarah E Medland 12 , Grant W Montgomery 26 , Dale R Nyholt 27 , Markus Perola 28 , Kirsi H Pietiläinen 29 , Veikko Salomaa 25 , Elina Sillanpää 30 , H Eka Suchiman 22 , Diana van Heemst 31 , Gonneke Willemsen 11 , Antonio Agudo 32 , Heiner Boeing 33 , Dorret I Boomsma 11 , Maria-Dolores Chirlaque 34 , Guy Fagherazzi 35 , Pietro Ferrari 36 , Paul Franks 37 , Christian Gieger 38 , Johan Gunnar Eriksson 39 , Marc Gunter 36 , Sara Hägg 14 , Iiris Hovatta 40 , Liher Imaz 41 , Jaakko Kaprio 42 , Rudolf Kaaks 43 , Timothy Key 44 , Vittorio Krogh 45 , Nicholas G Martin 12 , Olle Melander 46 , Andres Metspalu 19 , Concha Moreno 47 , N Charlotte Onland-Moret 48 , Peter Nilsson 49 , Ken K Ong 50 , Kim Overvad 51 , Domenico Palli 52 , Salvatore Panico 53 , Nancy L Pedersen 14 , Brenda W J H Penninx 17 , J Ramón Quirós 54 , Marjo Riitta Jarvelin 55 , Miguel Rodríguez-Barranco 56 , Robert A Scott 3 , Gianluca Severi 57 , P Eline Slagboom 10 , Tim D Spector 58 , Anne Tjonneland 59 , Antonia Trichopoulou 60 , Rosario Tumino 61 , André G Uitterlinden 7 , Yvonne T van der Schouw 48 , Cornelia M van Duijn 62 , Elisabete Weiderpass 36 , Eros Lazzerini Denchi 63 , Giuseppe Matullo 6 , Adam S Butterworth 64 , John Danesh 65 , Nilesh J Samani 2 , Nicholas J Wareham 3 , Christopher P Nelson 2 , Claudia Langenberg 3 , Veryan Codd 2
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2020-02-27 , DOI: 10.1016/j.ajhg.2020.02.006 Chen Li 1 , Svetlana Stoma 2 , Luca A Lotta 3 , Sophie Warner 4 , Eva Albrecht 5 , Alessandra Allione 6 , Pascal P Arp 7 , Linda Broer 7 , Jessica L Buxton 8 , Alexessander Da Silva Couto Alves 9 , Joris Deelen 10 , Iryna O Fedko 11 , Scott D Gordon 12 , Tao Jiang 13 , Robert Karlsson 14 , Nicola Kerrison 3 , Taylor K Loe 15 , Massimo Mangino 16 , Yuri Milaneschi 17 , Benjamin Miraglio 18 , Natalia Pervjakova 19 , Alessia Russo 6 , Ida Surakka 20 , Ashley van der Spek 21 , Josine E Verhoeven 17 , Najaf Amin 21 , Marian Beekman 22 , Alexandra I Blakemore 23 , Federico Canzian 24 , Stephen E Hamby 2 , Jouke-Jan Hottenga 11 , Peter D Jones 4 , Pekka Jousilahti 25 , Reedik Mägi 19 , Sarah E Medland 12 , Grant W Montgomery 26 , Dale R Nyholt 27 , Markus Perola 28 , Kirsi H Pietiläinen 29 , Veikko Salomaa 25 , Elina Sillanpää 30 , H Eka Suchiman 22 , Diana van Heemst 31 , Gonneke Willemsen 11 , Antonio Agudo 32 , Heiner Boeing 33 , Dorret I Boomsma 11 , Maria-Dolores Chirlaque 34 , Guy Fagherazzi 35 , Pietro Ferrari 36 , Paul Franks 37 , Christian Gieger 38 , Johan Gunnar Eriksson 39 , Marc Gunter 36 , Sara Hägg 14 , Iiris Hovatta 40 , Liher Imaz 41 , Jaakko Kaprio 42 , Rudolf Kaaks 43 , Timothy Key 44 , Vittorio Krogh 45 , Nicholas G Martin 12 , Olle Melander 46 , Andres Metspalu 19 , Concha Moreno 47 , N Charlotte Onland-Moret 48 , Peter Nilsson 49 , Ken K Ong 50 , Kim Overvad 51 , Domenico Palli 52 , Salvatore Panico 53 , Nancy L Pedersen 14 , Brenda W J H Penninx 17 , J Ramón Quirós 54 , Marjo Riitta Jarvelin 55 , Miguel Rodríguez-Barranco 56 , Robert A Scott 3 , Gianluca Severi 57 , P Eline Slagboom 10 , Tim D Spector 58 , Anne Tjonneland 59 , Antonia Trichopoulou 60 , Rosario Tumino 61 , André G Uitterlinden 7 , Yvonne T van der Schouw 48 , Cornelia M van Duijn 62 , Elisabete Weiderpass 36 , Eros Lazzerini Denchi 63 , Giuseppe Matullo 6 , Adam S Butterworth 64 , John Danesh 65 , Nilesh J Samani 2 , Nicholas J Wareham 3 , Christopher P Nelson 2 , Claudia Langenberg 3 , Veryan Codd 2
Affiliation
Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
中文翻译：
人类全基因组关联分析将核苷酸代谢与白细胞端粒长度联系起来。
白细胞端粒长度（LTL）是基因组衰老的遗传生物标志物。在这项研究中，我们通过汇集包括多达 78,592 名个体的大规模欧洲血统研究中的密集基因分型和推算关联结果，对 LTL 进行了全基因组荟萃分析。我们以错误发现率 (FDR) < 0.05 阈值识别出 49 个基因组区域，并优先考虑 31 个基因，其中 5 个突出显示核苷酸代谢是 LTL 的重要调节因子。我们报告了 SENP7、MOB1B、CARMIL1、PRRC2A、TERF2 和 RFWD3 中或附近的 6 个全基因组重要位点，并且我们的结果支持最近确定的 PARP1、POT1、ATM 和 MPHOSPH6 位点。对 >350,000 名英国生物银行参与者进行的全表型组分析表明，遗传上较短的端粒长度会增加患甲状腺功能减退症的风险，并降低患甲状腺癌、淋巴瘤和一系列增殖性疾病的风险。我们的结果重复了之前报道的与冠状动脉疾病风险增加和多种癌症类型风险降低的关联。我们的研究结果极大地扩展了目前对调节 LTL 的基因及其对人类健康和疾病的影响的认识。
更新日期：2020-02-27
中文翻译：
人类全基因组关联分析将核苷酸代谢与白细胞端粒长度联系起来。
白细胞端粒长度（LTL）是基因组衰老的遗传生物标志物。在这项研究中，我们通过汇集包括多达 78,592 名个体的大规模欧洲血统研究中的密集基因分型和推算关联结果，对 LTL 进行了全基因组荟萃分析。我们以错误发现率 (FDR) < 0.05 阈值识别出 49 个基因组区域，并优先考虑 31 个基因，其中 5 个突出显示核苷酸代谢是 LTL 的重要调节因子。我们报告了 SENP7、MOB1B、CARMIL1、PRRC2A、TERF2 和 RFWD3 中或附近的 6 个全基因组重要位点，并且我们的结果支持最近确定的 PARP1、POT1、ATM 和 MPHOSPH6 位点。对 >350,000 名英国生物银行参与者进行的全表型组分析表明，遗传上较短的端粒长度会增加患甲状腺功能减退症的风险，并降低患甲状腺癌、淋巴瘤和一系列增殖性疾病的风险。我们的结果重复了之前报道的与冠状动脉疾病风险增加和多种癌症类型风险降低的关联。我们的研究结果极大地扩展了目前对调节 LTL 的基因及其对人类健康和疾病的影响的认识。
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