John Paul Spence1, Dongbing Lai2, Jill L Reiter2, Sha Cao3, Richard L Bell4, Kent E Williams5, Tiebing Liang6. 1. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, 46202, United States. 2. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, United States. 3. Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, 46202, United States. 4. Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, 46202, United States. 5. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, United States. 6. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, United States. Electronic address: tliang@iu.edu.
Abstract
BACKGROUND: Paternal alcohol abuse is a well-recognized risk factor for the development of an alcohol use disorder (AUD). In addition to genetic and environmental risk factors, heritable epigenetic factors also have been proposed to play a key role in the development of AUD. However, it is not clear whether epigenetic factors contribute to the genetic inheritance in families affected by AUD. We used reciprocal crosses of the alcohol-preferring (P) and -nonpreferring (NP) rat lines to test whether epigenetic factors also impacted alcohol drinking in up to two generations of offspring. METHODS: F1 offspring derived by reciprocal breeding of P and NP rats were tested for differences in alcohol consumption using a free-choice protocol of 10% ethanol, 20% ethanol, and water that were available concurrently. In a separate experiment, an F2 population was tested for alcohol consumption not only due to genetic differences. These rats were generated from inbred P (iP) and iNP rat lines that were reciprocally bred to produce genetically identical F1 offspring that remained alcohol-naïve. Intercrosses of the F1 generation animals produced the F2 generation. Alcohol consumption was then assessed in the F2 generation using a standard two-bottle choice protocol, and was analyzed using genome-wide linkage analysis. Alcohol consumption measures were also analyzed for sex differences. RESULTS: Average alcohol consumption was higher in the F1 offspring of P vs. NP sires and in the F2 offspring of F0 iP vs. iNP grandsires. Linkage analyses showed the maximum LOD scores for alcohol consumption in both male and female offspring were on chromosome 4 (Chr 4). The LOD score for both sexes considered together was higher when the grandsire was iP vs. iNP (5.0 vs. 3.35, respectively). Furthermore, the F2 population displayed enhanced alcohol consumption when the P alleles from the F0 sire were present. CONCLUSIONS: These results demonstrate that epigenetic and/or non-genetic factors mapping to rat chromosome 4 contribute to a transgenerational paternal effect on alcohol consumption in the P and NP rat model of AUD.
BACKGROUND: Paternal alcohol abuse is a well-recognized risk factor for the development of an alcohol use disorder (AUD). In addition to genetic and environmental risk factors, heritable epigenetic factors also have been proposed to play a key role in the development of AUD. However, it is not clear whether epigenetic factors contribute to the genetic inheritance in families affected by AUD. We used reciprocal crosses of the alcohol-preferring (P) and -nonpreferring (NP) rat lines to test whether epigenetic factors also impacted alcohol drinking in up to two generations of offspring. METHODS: F1 offspring derived by reciprocal breeding of P and NPrats were tested for differences in alcohol consumption using a free-choice protocol of 10% ethanol, 20% ethanol, and water that were available concurrently. In a separate experiment, an F2 population was tested for alcohol consumption not only due to genetic differences. These rats were generated from inbred P (iP) and iNPrat lines that were reciprocally bred to produce genetically identical F1 offspring that remained alcohol-naïve. Intercrosses of the F1 generation animals produced the F2 generation. Alcohol consumption was then assessed in the F2 generation using a standard two-bottle choice protocol, and was analyzed using genome-wide linkage analysis. Alcohol consumption measures were also analyzed for sex differences. RESULTS: Average alcohol consumption was higher in the F1 offspring of P vs. NP sires and in the F2 offspring of F0 iP vs. iNP grandsires. Linkage analyses showed the maximum LOD scores for alcohol consumption in both male and female offspring were on chromosome 4 (Chr 4). The LOD score for both sexes considered together was higher when the grandsire was iP vs. iNP (5.0 vs. 3.35, respectively). Furthermore, the F2 population displayed enhanced alcohol consumption when the P alleles from the F0 sire were present. CONCLUSIONS: These results demonstrate that epigenetic and/or non-genetic factors mapping to rat chromosome 4 contribute to a transgenerational paternal effect on alcohol consumption in the P and NPrat model of AUD.
Authors: S Mahurkar; C Polytarchou; D Iliopoulos; C Pothoulakis; E A Mayer; L Chang Journal: Neurogastroenterol Motil Date: 2015-12-16 Impact factor: 3.598
Authors: T G Jenkins; E R James; D F Alonso; J R Hoidal; P J Murphy; J M Hotaling; B R Cairns; D T Carrell; K I Aston Journal: Andrology Date: 2017-09-26 Impact factor: 3.842
Authors: Tiebing Liang; John Spence; Lixiang Liu; Wendy N Strother; Hwai Wen Chang; Julie A Ellison; Lawrence Lumeng; Ting-Kai Li; Tatiana Foroud; Lucinda G Carr Journal: Proc Natl Acad Sci U S A Date: 2003-03-28 Impact factor: 11.205
Authors: L G Carr; T Foroud; P Bice; T Gobbett; J Ivashina; H Edenberg; L Lumeng; T K Li Journal: Alcohol Clin Exp Res Date: 1998-06 Impact factor: 3.455
Authors: Evangelos Evangelou; He Gao; Congying Chu; Georgios Ntritsos; Jimmy D Bell; Paul M Matthews; Adrian Rothenfluh; Sylvane Desrivières; Gunter Schumann; Paul Elliott; Paul Blakeley; Andrew R Butts; Raha Pazoki; Hideaki Suzuki; Fotios Koskeridis; Andrianos M Yiorkas; Ibrahim Karaman; Joshua Elliott; Qiang Luo; Stefanie Aeschbacher; Traci M Bartz; Sebastian E Baumeister; Peter S Braund; Michael R Brown; Jennifer A Brody; Toni-Kim Clarke; Niki Dimou; Jessica D Faul; Georg Homuth; Anne U Jackson; Katherine A Kentistou; Peter K Joshi; Rozenn N Lemaitre; Penelope A Lind; Leo-Pekka Lyytikäinen; Massimo Mangino; Yuri Milaneschi; Christopher P Nelson; Ilja M Nolte; Mia-Maria Perälä; Ozren Polasek; David Porteous; Scott M Ratliff; Jennifer A Smith; Alena Stančáková; Alexander Teumer; Samuli Tuominen; Sébastien Thériault; Jagadish Vangipurapu; John B Whitfield; Alexis Wood; Jie Yao; Bing Yu; Wei Zhao; Dan E Arking; Juha Auvinen; Chunyu Liu; Minna Männikkö; Lorenz Risch; Jerome I Rotter; Harold Snieder; Juha Veijola; Alexandra I Blakemore; Michael Boehnke; Harry Campbell; David Conen; Johan G Eriksson; Hans J Grabe; Xiuqing Guo; Pim van der Harst; Catharina A Hartman; Caroline Hayward; Andrew C Heath; Marjo-Riitta Jarvelin; Mika Kähönen; Sharon L R Kardia; Michael Kühne; Johanna Kuusisto; Markku Laakso; Jari Lahti; Terho Lehtimäki; Andrew M McIntosh; Karen L Mohlke; Alanna C Morrison; Nicholas G Martin; Albertine J Oldehinkel; Brenda W J H Penninx; Bruce M Psaty; Olli T Raitakari; Igor Rudan; Nilesh J Samani; Laura J Scott; Tim D Spector; Niek Verweij; David R Weir; James F Wilson; Daniel Levy; Ioanna Tzoulaki Journal: Nat Hum Behav Date: 2019-07-29
Authors: Patrick J Murphy; Jingtao Guo; Timothy G Jenkins; Emma R James; John R Hoidal; Thomas Huecksteadt; Dallin S Broberg; James M Hotaling; David F Alonso; Douglas T Carrell; Bradley R Cairns; Kenneth I Aston Journal: PLoS Genet Date: 2020-06-10 Impact factor: 5.917
Authors: Henry R Kranzler; Hang Zhou; Rachel L Kember; Rachel Vickers Smith; Amy C Justice; Scott Damrauer; Philip S Tsao; Derek Klarin; Aris Baras; Jeffrey Reid; John Overton; Daniel J Rader; Zhongshan Cheng; Janet P Tate; William C Becker; John Concato; Ke Xu; Renato Polimanti; Hongyu Zhao; Joel Gelernter Journal: Nat Commun Date: 2019-04-02 Impact factor: 14.919