Hui Ouyang1, Fang Han2, Zechen Zhou3, Qiwen Zheng3, Yangyang Wang1, Jun Zhang1. 1. Department of Neuromedicine, Peking University People's Hospital, Beijing 100044, China. 2. Department of Pulmonary Medicine, Peking University People's Hospital, Beijing 100044, China. 3. Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing 100191, China.
Abstract
BACKGROUND: Genome-wide association studies (GWASs) have identified a large number of single-nucleotide polymorphisms (SNPs) associated with narcolepsy. However, the sum impact of these SNPs on defining the genomic risk of narcolepsy remains unknown. In the present study, we investigated the associations between genetic risk scores (GRSs) and narcolepsy along with their predictive power. METHODS: A case-control study consisting of 903 narcolepsy patients and 1,981 healthy control subjects was performed. Thirty-two SNPs previously reported to confer susceptibility to narcolepsy were assessed for their association with narcolepsy risk. Subsequently, we constructed four GRS groups comprising reported narcolepsy susceptibility SNPs located in different genomic regions, and tested their association with narcolepsy risk using a regression model. Receiver operating characteristic (ROC) curves were used to examine the discriminatory power of the GRSs for predicting narcolepsy. RESULTS: Nine individual SNPs were significantly associated with narcolepsy after Bonferroni correction. All four GRSs were strongly associated with narcolepsy risk even when GRSs were constructed using SNPs located outside the previously implicated human leukocyte antigen (HLA) region on chromosome 6. The odds ratio (OR) for narcolepsy risk increased with the number of genetic loci implicated, ranging from an OR of 2.016 (95% CI, 1.657-2.456) to an OR of 4.298 (95% CI, 3.378-5.481). GRS4, constructed using the narcolepsy-associated SNPs identified in the Chinese population, was most closely associated with narcolepsy risk. CONCLUSIONS: The results suggest that the GRS method for combining common genetic variations can significantly associate GRS scores with narcolepsy risk and may facilitate narcolepsy risk stratification for prevention trials, both for HLA-DQB1*06:02-positive and -negative individuals. 2020 Annals of Translational Medicine. All rights reserved.
BACKGROUND: Genome-wide association studies (GWASs) have identified a large number of single-nucleotide polymorphisms (SNPs) associated with narcolepsy. However, the sum impact of these SNPs on defining the genomic risk of narcolepsy remains unknown. In the present study, we investigated the associations between genetic risk scores (GRSs) and narcolepsy along with their predictive power. METHODS: A case-control study consisting of 903 narcolepsy patients and 1,981 healthy control subjects was performed. Thirty-two SNPs previously reported to confer susceptibility to narcolepsy were assessed for their association with narcolepsy risk. Subsequently, we constructed four GRS groups comprising reported narcolepsy susceptibility SNPs located in different genomic regions, and tested their association with narcolepsy risk using a regression model. Receiver operating characteristic (ROC) curves were used to examine the discriminatory power of the GRSs for predicting narcolepsy. RESULTS: Nine individual SNPs were significantly associated with narcolepsy after Bonferroni correction. All four GRSs were strongly associated with narcolepsy risk even when GRSs were constructed using SNPs located outside the previously implicated human leukocyte antigen (HLA) region on chromosome 6. The odds ratio (OR) for narcolepsy risk increased with the number of genetic loci implicated, ranging from an OR of 2.016 (95% CI, 1.657-2.456) to an OR of 4.298 (95% CI, 3.378-5.481). GRS4, constructed using the narcolepsy-associated SNPs identified in the Chinese population, was most closely associated with narcolepsy risk. CONCLUSIONS: The results suggest that the GRS method for combining common genetic variations can significantly associate GRS scores with narcolepsy risk and may facilitate narcolepsy risk stratification for prevention trials, both for HLA-DQB1*06:02-positive and -negative individuals. 2020 Annals of Translational Medicine. All rights reserved.
Authors: C Capittini; A De Silvestri; M Terzaghi; V Scotti; C Rebuffi; A Pasi; R Manni; M Martinetti; C Tinelli Journal: Sleep Med Date: 2018-09-20 Impact factor: 3.492
Authors: Christian Fuchsberger; Jason Flannick; Tanya M Teslovich; Anubha Mahajan; Vineeta Agarwala; Kyle J Gaulton; Clement Ma; Pierre Fontanillas; Loukas Moutsianas; Davis J McCarthy; Manuel A Rivas; John R B Perry; Xueling Sim; Thomas W Blackwell; Neil R Robertson; N William Rayner; Pablo Cingolani; Adam E Locke; Juan Fernandez Tajes; Heather M Highland; Josee Dupuis; Peter S Chines; Cecilia M Lindgren; Christopher Hartl; Anne U Jackson; Han Chen; Jeroen R Huyghe; Martijn van de Bunt; Richard D Pearson; Ashish Kumar; Martina Müller-Nurasyid; Niels Grarup; Heather M Stringham; Eric R Gamazon; Jaehoon Lee; Yuhui Chen; Robert A Scott; Jennifer E Below; Peng Chen; Jinyan Huang; Min Jin Go; Michael L Stitzel; Dorota Pasko; Stephen C J Parker; Tibor V Varga; Todd Green; Nicola L Beer; Aaron G Day-Williams; Teresa Ferreira; Tasha Fingerlin; Momoko Horikoshi; Cheng Hu; Iksoo Huh; Mohammad Kamran Ikram; Bong-Jo Kim; Yongkang Kim; Young Jin Kim; Min-Seok Kwon; Juyoung Lee; Selyeong Lee; Keng-Han Lin; Taylor J Maxwell; Yoshihiko Nagai; Xu Wang; Ryan P Welch; Joon Yoon; Weihua Zhang; Nir Barzilai; Benjamin F Voight; Bok-Ghee Han; Christopher P Jenkinson; Teemu Kuulasmaa; Johanna Kuusisto; Alisa Manning; Maggie C Y Ng; Nicholette D Palmer; Beverley Balkau; Alena Stančáková; Hanna E Abboud; Heiner Boeing; Vilmantas Giedraitis; Dorairaj Prabhakaran; Omri Gottesman; James Scott; Jason Carey; Phoenix Kwan; George Grant; Joshua D Smith; Benjamin M Neale; Shaun Purcell; Adam S Butterworth; Joanna M M Howson; Heung Man Lee; Yingchang Lu; Soo-Heon Kwak; Wei Zhao; John Danesh; Vincent K L Lam; Kyong Soo Park; Danish Saleheen; Wing Yee So; Claudia H T Tam; Uzma Afzal; David Aguilar; Rector Arya; Tin Aung; Edmund Chan; Carmen Navarro; Ching-Yu Cheng; Domenico Palli; Adolfo Correa; Joanne E Curran; Denis Rybin; Vidya S Farook; Sharon P Fowler; Barry I Freedman; Michael Griswold; Daniel Esten Hale; Pamela J Hicks; Chiea-Chuen Khor; Satish Kumar; Benjamin Lehne; Dorothée Thuillier; Wei Yen Lim; Jianjun Liu; Yvonne T van der Schouw; Marie Loh; Solomon K Musani; Sobha Puppala; William R Scott; Loïc Yengo; Sian-Tsung Tan; Herman A Taylor; Farook Thameem; Gregory Wilson; Tien Yin Wong; Pål Rasmus Njølstad; Jonathan C Levy; Massimo Mangino; Lori L Bonnycastle; Thomas Schwarzmayr; João Fadista; Gabriela L Surdulescu; Christian Herder; Christopher J Groves; Thomas Wieland; Jette Bork-Jensen; Ivan Brandslund; Cramer Christensen; Heikki A Koistinen; Alex S F Doney; Leena Kinnunen; Tõnu Esko; Andrew J Farmer; Liisa Hakaste; Dylan Hodgkiss; Jasmina Kravic; Valeriya Lyssenko; Mette Hollensted; Marit E Jørgensen; Torben Jørgensen; Claes Ladenvall; Johanne Marie Justesen; Annemari Käräjämäki; Jennifer Kriebel; Wolfgang Rathmann; Lars Lannfelt; Torsten Lauritzen; Narisu Narisu; Allan Linneberg; Olle Melander; Lili Milani; Matt Neville; Marju Orho-Melander; Lu Qi; Qibin Qi; Michael Roden; Olov Rolandsson; Amy Swift; Anders H Rosengren; Kathleen Stirrups; Andrew R Wood; Evelin Mihailov; Christine Blancher; Mauricio O Carneiro; Jared Maguire; Ryan Poplin; Khalid Shakir; Timothy Fennell; Mark DePristo; Martin Hrabé de Angelis; Panos Deloukas; Anette P Gjesing; Goo Jun; Peter Nilsson; Jacquelyn Murphy; Robert Onofrio; Barbara Thorand; Torben Hansen; Christa Meisinger; Frank B Hu; Bo Isomaa; Fredrik Karpe; Liming Liang; Annette Peters; Cornelia Huth; Stephen P O'Rahilly; Colin N A Palmer; Oluf Pedersen; Rainer Rauramaa; Jaakko Tuomilehto; Veikko Salomaa; Richard M Watanabe; Ann-Christine Syvänen; Richard N Bergman; Dwaipayan Bharadwaj; Erwin P Bottinger; Yoon Shin Cho; Giriraj R Chandak; Juliana C N Chan; Kee Seng Chia; Mark J Daly; Shah B Ebrahim; Claudia Langenberg; Paul Elliott; Kathleen A Jablonski; Donna M Lehman; Weiping Jia; Ronald C W Ma; Toni I Pollin; Manjinder Sandhu; Nikhil Tandon; Philippe Froguel; Inês Barroso; Yik Ying Teo; Eleftheria Zeggini; Ruth J F Loos; Kerrin S Small; Janina S Ried; Ralph A DeFronzo; Harald Grallert; Benjamin Glaser; Andres Metspalu; Nicholas J Wareham; Mark Walker; Eric Banks; Christian Gieger; Erik Ingelsson; Hae Kyung Im; Thomas Illig; Paul W Franks; Gemma Buck; Joseph Trakalo; David Buck; Inga Prokopenko; Reedik Mägi; Lars Lind; Yossi Farjoun; Katharine R Owen; Anna L Gloyn; Konstantin Strauch; Tiinamaija Tuomi; Jaspal Singh Kooner; Jong-Young Lee; Taesung Park; Peter Donnelly; Andrew D Morris; Andrew T Hattersley; Donald W Bowden; Francis S Collins; Gil Atzmon; John C Chambers; Timothy D Spector; Markku Laakso; Tim M Strom; Graeme I Bell; John Blangero; Ravindranath Duggirala; E Shyong Tai; Gilean McVean; Craig L Hanis; James G Wilson; Mark Seielstad; Timothy M Frayling; James B Meigs; Nancy J Cox; Rob Sladek; Eric S Lander; Stacey Gabriel; Noël P Burtt; Karen L Mohlke; Thomas Meitinger; Leif Groop; Goncalo Abecasis; Jose C Florez; Laura J Scott; Andrew P Morris; Hyun Min Kang; Michael Boehnke; David Altshuler; Mark I McCarthy Journal: Nature Date: 2016-07-11 Impact factor: 69.504