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Multidimensional Genetic Analysis of Repeated Seizures in the Hybrid Mouse Diversity Panel 10 Reveals a Novel Epileptogenesis Susceptibility Locus

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Multidimensional Genetic Analysis of Repeated Seizures in the Hybrid Mouse Diversity Panel 10 Reveals a Novel Epileptogenesis Susceptibility Locus G3: Genes|Genomes|Genetics Early Online, published on June 15, 2017 as doi:10.1534/g3.117.042234 1 2 3 4 5 6 7 8 9 Multidimensional genetic analysis of repeated seizures in the hybrid mouse diversity panel 10 reveals a novel epileptogenesis susceptibility locus. 11 Russell J Ferland*, †, ‡, Jason Smith§, Dominick Papandrea‡, Jessica Gracias††, Leah 12 Hains§, Sridhar B Kadiyala*, Brittany O’Brien††, Eun Yong Kang‡‡, Barbara S Beyer*, and Bruce 13 J Herron§,†† 14 15 * Department of Neuroscience and Experimental Therapeutics, Albany Medical College, 16 Albany, New York 12208 17 † Department of Neurology, Albany Medical College, Albany, New York 12208 18 ‡ Department of Biological Sciences, Center for Biotechnology and Interdisciplinary 19 Studies, Rensselaer Polytechnic Institute, Troy, New York 12180 20 § Wadsworth Center, Albany, New York 12201 21 †† Department of Biomedical Sciences, School of Public Health, SUNY Albany, Albany, New 22 York 12201 23 ‡‡ Department of Computer Science, University of California, Los Angeles, CA, USA 24 90095 25 © The Author(s) 2013. Published by the Genetics Society of America. 26 27 28 Short running title: Camta1 modifies epileptogenesis 29 Keywords: Genetics 30 Epilepsy 31 Preclinical model 32 Neuronal plasticity 33 Complex traits 34 35 36 Correspondence to either: 37 38 Russell J. Ferland, PhD Bruce J. Herron, PhD 39 Albany Medical College Center for Medical Sciences 40 Department of Neuroscience and Wadsworth Center, NYS Dept. of Health 41 Experimental Therapeutics 150 New Scotland Ave 42 47 New Scotland Avenue, MC-136 Albany, NY 12208 43 Albany, NY 12208 [email protected] 44 [email protected] 45 46 47 48 49 50 Conflict of Interest: The authors declare no competing financial interests. 51 52 Acknowledgements: This work was supported by an NIH/NINDS R01NS064283 grant to RJF. 53 We are grateful to Veterinary Sciences at the Wadsworth Center and Albany Medical College 54 that supported the completion of this work. We also thank Dr. Rob Williams for helpful 55 discussion during the progress of this study. The exceptional animal husbandry expertise 56 of Barbara Beyer, who has since passed away, was critical to the success of this 57 project. 2 58 Abstract 59 Epilepsy has many causes and comorbidities affecting as many as 4% of people in their lifetime. 60 Both idiopathic and symptomatic epilepsies are highly heritable, but genetic factors are difficult 61 to characterize among humans due to complex disease etiologies. Rodent genetic studies have 62 been critical to the discovery of seizure susceptibility loci, including Kcnj10 mutations identified 63 in both mouse and human cohorts. However, genetic analyses of epilepsy phenotypes in mice 64 to date have been carried out as acute studies in seizure-naive animals or in Mendelian models 65 of epilepsy, while humans with epilepsy have a history of recurrent seizures that also modify 66 brain physiology. We have applied a repeated seizure model to a genetic reference population, 67 following seizure susceptibility over a 36-day period. Initial differences in generalized seizure 68 threshold among the Hybrid Mouse Diversity Panel were associated with a well-characterized 69 seizure susceptibility locus found in mice; Seizure susceptibility 1. Remarkably, Szs1 influence 70 diminished as subsequent induced seizures had diminishing latencies in certain HMDP strains. 71 Administration of eight seizures, followed by an incubation period and an induced retest seizure, 72 revealed novel associations within the calmodulin-activated transcription factor 1, Camta1. Using 73 systems genetics, we have identified 4 candidate genes that are differentially expressed 74 between seizure-sensitive and -resistant strains close to Esf1 that may act individually or as a 75 coordinated response to the neuronal stress of seizures. 3 76 Significance Statement 77 Epileptogenesis is a complex trait with a partially characterized genetic basis. While recurrent 78 seizures define epilepsy, no preclinical epilepsy models have investigated if repeated seizures 79 contribute to disease progression. We used genome-wide association studies in mice to uncover 80 genetic factors that mediate acute seizure susceptibility and those dependent on repeated 81 seizures. We found that seizure-naive animals have seizure susceptibilities consistent with other 82 experimental epilepsy models. However, inducing repeated seizures shifts genetic associations 83 to a novel genomic region containing genes suitable for facilitating epileptogenesis. We show 84 that initial seizures likely contribute to epileptogenesis susceptibility and have utilized systems- 85 genetics to identify epileptogenesis candidate genes. 4 86 Introduction 87 Epilepsies in humans are highly heritable syndromes that are modified by complex 88 interactions between genes and the environment. In the US, approximately 2.2 million people 89 will develop some form of epilepsy during their lifetime (England et al. 2012). Despite diverse 90 treatments options, largely focused on seizure suppression, individuals with epilepsy suffer 91 multiple quality of life issues, refractory seizures, comorbid complications, and a higher incidence 92 of sudden death (Gupta et al. 2016). Understanding interactions between genetic seizure 93 susceptibility loci and environmental stressors induced by repeated seizures will uncover novel 94 mechanisms of epilepsy pathogenesis. This information will improve therapeutic options by 95 focusing treatment on epileptogenesis (Ferraro 2015). 96 Identification of gene by environment interactions for individuals with epilepsy is limited by 97 complex disease etiologies, and the inability to identify at risk populations prior to disease onset. 98 Consequently, the majority of epilepsy genome wide association studies (GWAS) carried out to 99 date compare affected populations to seizure-naive controls rather than following epilepsy 100 progression in a population from a seizure-naive to an epileptic state (International League 101 Against Epilepsy Consortium on Complex Epilepsies. 2014). Experimental seizure paradigms 102 can overcome such limitations to discover the genetic basis of epileptogenesis. 103 Preclinical epilepsy models have implicated multiple gene mutations as contributors to 104 seizure disorders. This success is due in part to strong genetic influences that segregate among 105 rodent models of seizure susceptibility (Engstrom and Woodbury 1988; Kosobud and Crabbe 106 1990). Unfortunately, most of these models utilized either acute seizure measurements or status 107 epilepticus as quantitative measures of seizure susceptibility (Grone and Baraban 2015). 108 Alternatively, animal models that measure epileptogenesis and other models of brain plasticity 109 are typically designed to minimize genetic background effects (Grone and Baraban 2015). 5 110 Notably, while numerous hyperexcitability factors are now known, genetic factors influencing 111 epileptogenesis remain largely uncharacterized. 112 We have utilized a repeated flurothyl-induced seizure model delivered to the Hybrid Mouse 113 Diversity Panel (HMDP) to identify genetic susceptibility factors that modify epileptogenesis 114 (Papandrea et al. 2009). Genetic differences in initial flurothyl-induced seizures were consistent 115 with previous studies showing the strongest quantitative trait loci (QTL) mapping to the Szs1 116 locus (Ferraro et al. 1997, 2004; Chaix et al. 2007). Surprisingly, as additional seizures were 117 administered to this population, the effects of Szs1 diminished, and genetic associations on 118 distal chromosome 4 garnered influence over seizure susceptibility. We attribute the shift in 119 susceptibility to seizure-related changes in brain plasticity that are modified by gene(s) that may 120 mitigate the effects of Szs1. This hypothesis is supported by interactions between Szs1 and our 121 novel epileptogenesis susceptibility locus on chromosome 4; Epileptogenesis susceptibility 122 factor 1 (Esf1). Systems genetics analysis of the Esf1 region has uncovered a co-regulated set 123 of expression QTL (eQTL) that have been implicated in neurological stress response that are 124 now also implicated in epileptogenesis. 125 126 Materials and Methods 127 Animals. The rationale for using the HMDP and its advantages with respect to statistical power 128 and genetic resolution have been previously described (Bennett et al. 2010). The inbred strains 129 of mice that were used for this study include the following: Balb/cJ (Balb; n = 8); BTBR T+Ltpr3tf/J 130 (BTBR; n = 6); BXD#/TyJ (BXD#; 30 strains, average n/strain ≤ 6 ); BXD##/RwwJ (BXD##; 18 131 strains, average n/strain ≤ 4); C57BL/6J (B6; n = 10); C57BL/10SNJ (10SNJ; n = 12); C57BL/10J 132 (10J; n = 8); C57BL/6NJ (6NJ; n= 16); C57BLKS/J (KS/J; n = 15); CAST/EiJ (CAST; n = 6); 133 CBA/J (CBA; n = 17); CE/J (CE; n = 11); DBA/2J (D2; n = 14); FVB/NJ (FVB; n = 12); LG/J (LG; 6 134 n = 19); MRL/MpJ (MRL; n = 6); NOD/ShiLtJ (NOD; n = 13); NZW/LacJ (NZW; n = 10); PWD/PhJ 135 (PWD; n = 9) and Sm/J (Sm; n = 13). Male and female mice were obtained from the Jackson 136 Laboratories (Bar Harbor, ME, USA) and 1) were acclimated to the animal facility for one week 137 before seizure testing commenced, or 2) were further bred at the Wadsworth Center and 138 exposed to the repeated-flurothyl seizure model. Mice were housed on a 12 hr light-dark cycle 139 with ad libitum access to food and water. 140 A [B6XD2]F2 cross was generated by intercrossing [B6XD2]F1 parents. Both male
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