Abstract
Non-obstructive azoospermia (NOA), a severe form of male infertility, is often suspected to be linked to currently undefined genetic abnormalities. To explore the genetic basis of this condition, we successfully sequenced ~650 infertility-related genes in 757 NOA patients and 709 fertile males. We evaluated the contributions of rare variants to the etiology of NOA by identifying individual genes showing nominal associations and testing the genetic burden of a given biological process as a whole. We found a significant excess of rare, non-silent variants in genes that are key epigenetic regulators of spermatogenesis, such as BRWD1, DNMT1, DNMT3B, RNF17, UBR2, USP1 and USP26, in NOA patients (P = 5.5 × 10(-7)), corresponding to a carrier frequency of 22.5% of patients and 13.7% of controls (P = 1.4 × 10(-5)). An accumulation of low-frequency variants was also identified in additional epigenetic genes (BRDT and MTHFR). Our study suggested the potential associations of genetic defects in genes that are epigenetic regulators with spermatogenic failure in human.
References
Feb 20, 1997·The New England Journal of Medicine·J L PryorK P Roberts
Nov 11, 1999·Cell·M OkanoE Li
Feb 22, 2001·Human Molecular Genetics·Z ChenR Rozen
Jan 11, 2002·Developmental Biology·Hisaaki TakahashiToshikazu Nakamura
May 26, 2004·Lancet·Cristina Joana MarquesAlberto Barros
Jul 24, 2004·International Journal of Andrology·M SimoniC Krausz
Nov 5, 2004·Cellular and Molecular Life Sciences : CMLS·A HermannA Jeltsch
Apr 1, 2005·Nature·Sarah Kimmins, Paolo Sassone-Corsi
Aug 12, 2005·Development·Jieyan PanP Jeremy Wang
Dec 6, 2005·Cell·Sebastian M B NijmanRené Bernards
Jun 21, 2007·Reproductive Biomedicine Online·Alberto FerlinCarlo Foresta
Aug 31, 2007·Development·Enyuan ShangDebra J Wolgemuth
Mar 21, 2008·Developmental Biology·Dana L PhilippsJohn C Schimenti
Nov 8, 2008·Nature Medicine·Martin M Matzuk, Dolores J Lamb
May 30, 2009·Journal of Andrology·Kenneth I Aston, Douglas T Carrell
Sep 25, 2009·Reproduction : the Official Journal of the Society for the Study of Fertility·Liesbeth Visser, Sjoerd Repping
Nov 26, 2009·American Journal of Human Genetics·Brian L Browning, Zhaoxia Yu
May 19, 2010·Nature Reviews. Genetics·Elizabeth T Cirulli, David B Goldstein
Jun 2, 2010·Canadian Urological Association Journal = Journal De L'Association Des Urologues Du Canada·Keith JarviVictor Mak
Jul 6, 2010·Journal of Experimental & Clinical Cancer Research : CR·Wei LiHongfa Yang
Jul 27, 2010·Nature Genetics·Christopher T JohansenRobert A Hegele
Oct 14, 2010·Nature Reviews. Genetics·Vikas BansalNicholas J Schork
Oct 29, 2010·Biology of Reproduction·Mingang Xu, Norman B Hecht
Nov 5, 2010·Human Molecular Genetics·Monica MencarelliKarine Clement
May 5, 2011·Mutation Research·Singh RajenderAshok Agarwal
May 10, 2011·Human Molecular Genetics·Chicheng SunChia-Hsiang Chen
Dec 27, 2011·Nature Genetics·Zhibin HuJiahao Sha
Feb 9, 2013·Human Molecular Genetics·Anath C LionelStephen W Scherer
Aug 21, 2013·Advances in Experimental Medicine and Biology·John R GannonDouglas T Carrell
May 20, 2014·Cell Stem Cell·Saher Sue HammoudBradley R Cairns
Citations
Aug 5, 2015·Proceedings of the National Academy of Sciences of the United States of America·Priti Singh, John C Schimenti
Oct 9, 2015·Reproduction : the Official Journal of the Society for the Study of Fertility·Csilla KrauszChiara Chianese
Jul 25, 2015·PloS One·Lisha MouYaoting Gui
Jun 22, 2016·Prenatal Diagnosis·Katherine BiancoSusan J Fisher
Oct 7, 2016·Molecular Immunology·Ronald SchilderinkWouter J de Jonge
Nov 5, 2016·Biochemical and Biophysical Research Communications·Shirly Lahav-BaratzAaron Ciechanover
Jan 26, 2016·Scientific Reports·Jing LuXinru Wang
Nov 10, 2015·Scientific Reports·Motoko MaekawaTakeo Yoshikawa
Apr 20, 2016·Reproductive Sciences·Qian MaYaoting Gui
Apr 7, 2018·Nature Reviews. Urology·Csilla Krausz, Antoni Riera-Escamilla
Nov 28, 2017·Andrology·K ShiraishiH Matsuyama
Nov 10, 2015·Scientific Reports·Kang LiuJie Li
Sep 4, 2019·Andrology·T F AraujoF Tüttelmann
Sep 26, 2019·Scientific Reports·Kohei SakaiTohru Kimura
Dec 10, 2019·Science China. Life Sciences·Lu WenZi-Jiang Chen
Aug 21, 2020·BMC Biology·Matthew J RobertsonThomas X Garcia
Feb 18, 2017·Genetic Epidemiology·Nicholas B LarsonDaniel J Schaid
Sep 18, 2020·Stem Cell Reviews and Reports·Shumin ZhouShuiqiao Yuan
Mar 20, 2019·Chromosoma·Natalia Felipe-MedinaAlberto M Pendás
Aug 9, 2016·Molecular Medicine Reports·Lisha Mou, Yaoting Gui
Jun 6, 2020·Medicine·Qi XiHongguo Zhang
Nov 17, 2020·Human Reproduction Update·Antonio CapalboCarlos Simon
Feb 27, 2021·Scientific Reports·Qian MaYaoting Gui
Dec 2, 2020·Journal of Hazardous Materials·Abik Nandi, Debapratim Kar Chowdhuri
Jul 3, 2021·Cells·Chunyu LiuYunxia Cao
Jun 28, 2021·Reproductive Biology and Endocrinology : RB&E·Zhiming LiShuiqiao Yuan