Genetic Modifiers of Neurological Disease


Genetic modifiers make a significant contribution to the pathophysiology of neurological disease. A common feature of heritable neurological disease is phenotype variation among patients with the same mutation. Some of the observed phenotype variation can be attributed to genetic modifiers. Identifying modifier genes in humans is challenging due to limitations of sample size and confounding environmental effects. Complementary approaches in model organisms can facilitate the identification and characterisation of modifier genes. Identifying genetic modifiers can help elucidate the genetic and molecular basis of neurological disease. This knowledge can be used to improve genetic risk assessment and foster the development of personalised therapeutic strategies based on molecular diagnosis.

Key Concepts:

  • Genetic modifiers contribute to phenotype variability in neurological disorders.

  • Model organisms are a useful system for identifying modifier genes and studying underlying mechanisms.

  • Synergy between human genetics and model systems can facilitate modifier gene identification and validation.

  • Identifying pathways that are influenced by gene modifiers may suggest novel therapeutic strategies.

Keywords: modifier gene; genetics; neurological disease; nervous system disease; disease models; mice

Figure 1.

Integrated approach to identifying genetic modifiers of neurological disease. Primary neurological disease genes that have been identified in human patients can be introduced into model systems using available genetic tools. Model organisms can be used to screen for genetic modifiers that influence the phenotype. Genetic modifiers identified in model systems can then be tested for disease association in humans. Similarly, genetic modifiers identified in humans can be confirmed and studied in model systems.

Figure 2.

Genetic modifiers in mouse models. Systematic crossing of mouse models to different inbred strain backgrounds can reveal strain‐dependent phenotype variation, providing evidence that genetic modifiers contribute to phenotype expression. For this approach it is common to perform a strain survey, in which a mouse mutant (m/+, white) is crossed to wild‐type mice from different inbred strain backgrounds colors. F1 mutant offspring are examined for differences in phenotype compared to the mutant phenotype on the parental strain. Phenotype exacerbation or improvement provides suggestive evidence that an inbred strain carries modifier alleles. If the inbred strain background does not carry modifier variants, the phenotype will be unaltered.

Figure 3.

Interval‐specific congenic strains for fine mapping of modifier genes. The mapped interval from the strain carrying the modifier locus (donor, blue) is introgressed onto the unmodified strain background (recipient, red) by selective genotyping and breeding for at least five generations. Several lines carrying varying segments of the modifier interval are tested for the ability to modify the mutant phenotype in order to localise the critical interval. Line C (light blue) confers the modified phenotype, localising the modifier to the small region that is nonoverlapping with line B (star).



Achilli F, Bros‐Facer V, Williams HP et al. (2009) An ENU‐induced mutation in mouse glycyl‐tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot–Marie–Tooth type 2D peripheral neuropathy. Disease Models and Mechanisms 2(7–8): 359–373.

Ahmad ST, Sweeney ST, Lee JA et al. (2009) Genetic screen identifies serpin5 as a regulator of the toll pathway and CHMP2B toxicity associated with frontotemporal dementia. Proceedings of the National Academy of Sciences of the USA 106(29): 12168–12173.

Andrew SE, Goldberg YP, Kremer B et al. (1993) The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nature Genetics 4(4): 398–403.

Au KS, Ward CH and Northrup H (2008) Tuberous sclerosis complex: disease modifiers and treatments. Current Opinion in Pediatrics 20(6): 628–633.

Bergren SK, Chen S, Galecki A et al. (2005) Genetic modifiers affecting severity of epilepsy caused by mutation of sodium channel Scn2a. Mammalian Genome 16(9): 683–690.

Bergren SK, Rutter ED and Kearney JA (2009) Fine mapping of an epilepsy modifier gene on mouse Chromosome 19. Mammalian Genome 20(6): 359–366.

Branco J, Al‐Ramahi I, Ukani L et al. (2008) Comparative analysis of genetic modifiers in Drosophila points to common and distinct mechanisms of pathogenesis among polyglutamine diseases. Human Molecular Genetics 17(3): 376–390.

Buchner DA, Trudeau M, George AL et al. (2003a) High‐resolution mapping of the sodium channel modifier Scnm1 on mouse chromosome 3 and identification of a 1.3‐kb recombination hot spot. Genomics 82(4): 452–459.

Buchner DA, Trudeau M and Meisler MH (2003b) SCNM1, a putative RNA splicing factor that modifies disease severity in mice. Science 301(5635): 967–969.

Carlson GA, Borchelt DR, Dake A et al. (1997) Genetic modification of the phenotypes produced by amyloid precursor protein overexpression in transgenic mice. Human Molecular Genetics 6(11): 1951–1959.

Djousse L, Knowlton B, Hayden MR et al. (2004) Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16. Neurogenetics 5(2): 109–114.

Duyao M, Ambrose C, Myers R et al. (1993) Trinucleotide repeat length instability and age of onset in Huntington's disease. Nature Genetics 4(4): 387–392.

Giess R, Holtmann B, Braga M et al. (2002) Early onset of severe familial amyotrophic lateral sclerosis with a SOD‐1 mutation: potential impact of CNTF as a candidate modifier gene. American Journal of Human Genetics 70(5): 1277–1286.

Gusella JF and MacDonald ME (2009) Huntington's disease: the case for genetic modifiers. Genome Medicine 1(8): 80.

Guy J, Hendrich B, Holmes M et al. (2001) A mouse Mecp2‐null mutation causes neurological symptoms that mimic Rett syndrome. Nature Genetics 27(3): 322–326.

van Ham TJ, Thijssen KL, Breitling R et al. (2008) C. elegans model identifies genetic modifiers of alpha‐synuclein inclusion formation during aging. PLoS Genetics 4(3): e1000027

Hawkins NA, Martin MS, Frankel WN et al. (2011) Neuronal voltage‐gated ion channels are genetic modifiers of generalized epilepsy with febrile seizures plus. Neurobiology of Disease 41(3): 655–660.

Heiman‐Patterson TD, Deitch JS, Blankenhorn EP et al. (2005) Background and gender effects on survival in the TgN(SOD1‐G93A)1Gur mouse model of ALS. Journal of the Neurological Sciences 236(1–2): 1–7.

Howell VM, Jones JM, Bergren SK et al. (2007) Evidence for a direct role of the disease modifier SCNM1 in splicing. Human Molecular Genetics 16(20): 2506–2516.

Jorge BS, Campbell CM, Miller AR et al. (2011) Voltage‐gated potassium channel KCNV2 (Kv8.2) contributes to epilepsy susceptibility. Proceedings of the National Academy of Sciences of the USA 108(13): 5443–5448.

Jung J, van Jaarsveld MT, Shieh SY et al. (2011) Defining genetic factors that modulate intergenerational CAG repeat instability in Drosophila melanogaster. Genetics 187(1): 61–71.

Kearney JA (2011) Genetic modifiers of neurological disease. Current Opinion in Genetics & Development 21(3): 349–353.

Kearney JA, Buchner DA, De Haan G et al. (2002) Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Na(v)1.6). Human Molecular Genetics 11(22): 2765–2775.

Klassen T, Davis C, Goldman A et al. (2011) Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Cell 145(7): 1036–1048.

Kohrman DC, Harris JB and Meisler MH (1996) Mutation detection in the med and medJ alleles of the sodium channel Scn8a. Unusual splicing due to a minor class AT‐AC intron. Journal of Biological Chemistry 271(29): 17576–17581.

Kraemer BC, Burgess JK, Chen JH et al. (2006) Molecular pathways that influence human tau‐induced pathology in Caenorhabditis elegans. Human Molecular Genetics 15(9): 1483–1496.

Krezowski J, Knudson D, Ebeling C et al. (2004) Identification of loci determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression. Human Molecular Genetics 13(18): 1989–1997.

Lambrechts D, Storkebaum E, Morimoto M et al. (2003) VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nature Genetics 34(4): 383–394.

Lee I, Lehner B, Vavouri T et al. (2010) Predicting genetic modifier loci using functional gene networks. Genome Research 20(8): 1143–1153.

Li JL, Hayden MR, Almqvist EW et al. (2003) A genome scan for modifiers of age at onset in Huntington disease: the HD MAPS study. American Journal of Human Genetics 73(3): 682–687.

Lloret A, Dragileva E, Teed A et al. (2006) Genetic background modifies nuclear mutant huntingtin accumulation and HD CAG repeat instability in Huntington's disease knock‐in mice. Human Molecular Genetics 15(12): 2015–2024.

Lorenzetti D, Watase K, Xu B et al. (2000) Repeat instability and motor incoordination in mice with a targeted expanded CAG repeat in the Sca1 locus. Human Molecular Genetics 9(5): 779–785.

Meisler MH and Kearney JA (2005) Sodium channel mutations in epilepsy and other neurological disorders. Journal of Clinical Investigation 115(8): 2010–2017.

Metzger S, Saukko M, Van Che H et al. (2010) Age at onset in Huntington's disease is modified by the autophagy pathway: implication of the V471A polymorphism in Atg7. Human Genetics 128(4): 453–459.

Nissim‐Rafinia M and Kerem B (2005) The splicing machinery is a genetic modifier of disease severity. Trends in Genetics 21(9): 480–483.

Nollen EA, Garcia SM, van Haaften G et al. (2004) Genome‐wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation. Proceedings of the National Academy of Sciences of the USA 101(17): 6403–6408.

Perez FA and Palmiter RD (2005) Parkin‐deficient mice are not a robust model of parkinsonism. Proceedings of the National Academy of Sciences of the USA 102(6): 2174–2179.

Riboldi G, Nizzardo M, Simone C et al. (2011) ALS genetic modifiers that increase survival of SOD1 mice and are suitable for therapeutic development. Progress in Neurobiology 95(2): 133–148.

Risch NJ, Bressman SB, Senthil G et al. (2007) Intragenic cis and trans modification of genetic susceptibility in DYT1 torsion dystonia. American Journal of Human Genetics 80(6): 1188–1193.

Rubinsztein DC (2008) Functional genomics approaches to neurodegenerative diseases. Mammalian Genome 19(9): 587–590.

Shalom A and Darvasi A (2002) Experimental designs for QTL fine mapping in rodents. Methods in Molecular Biology 195: 199–223.

Snell RG, MacMillan JC, Cheadle JP et al. (1993) Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease. Nature Genetics 4(4): 393–397.

Sprunger LK, Escayg A, Tallaksen‐Greene S et al. (1999) Dystonia associated with mutation of the neuronal sodium channel Scn8a and identification of the modifier locus Scnm1 on mouse chromosome 3. Human Molecular Genetics 8(3): 471–479.

Teuling E, Bourgonje A, Veenje S et al. (2011) Modifiers of mutant huntingtin aggregation: functional conservation of C. elegans‐modifiers of polyglutamine aggregation. PLoS Currents 3: RRN1255.

Treusch S, Hamamichi S, Goodman JL et al. (2011) Functional links between Abeta toxicity, endocytic trafficking, and Alzheimer's disease risk factors in yeast. Science 334(6060): 1241–1245.

Valente EM, Silhavy JL, Brancati F et al. (2006) Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome. Nature Genetics 38(6): 623–625.

Van Raamsdonk JM, Metzler M, Slow E et al. (2007) Phenotypic abnormalities in the YAC128 mouse model of Huntington disease are penetrant on multiple genetic backgrounds and modulated by strain. Neurobiology of Disease 26(1): 189–200.

Wang J, Farr GW, Zeiss CJ et al. (2009) Progressive aggregation despite chaperone associations of a mutant SOD1‐YFP in transgenic mice that develop ALS. Proceedings of the National Academy of Sciences of the USA 106(5): 1392–1397.

Wexler NS, Lorimer J, Porter J et al. (2004) Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. Proceedings of the National Academy of Sciences of the USA 101(10): 3498–3503.

Yu FH, Mantegazza M, Westenbroek RE et al. (2006) Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nature Neuroscience 9(9): 1142–1149.

Further Reading

Gusella JF and MacDonald ME (2011) Huntington's disease: seeing the pathogenic process through a genetic lens. Trends in Biochemical Sciences 31(9): 533–540.

Heiman‐Patterson TD, Sher RB, Blankenhorn EA et al. (2011) Effect of genetic background on phenotype variability in transgenic mouse models of amyotrophic lateral sclerosis: a window of opportunity in the search for genetic modifiers. Amyotrophic Lateral Sclerosis 12(2): 79–86.

McGurk L and Bonini NM (2011) Yeast informs Alzheimer's disease. Science 334: 1212–1213.

Meisler MH, O'Brien JE and Sharkey LM (2010) Sodium channel gene family: epilepsy mutations, gene interactions and modifier effects. Journal of Physiology 588(part 11): 184108.

Miller‐Fleming L, Giorgini F and Outeiro TF (2008) Yeast as a model for studying human neurodegenerative disorders. Biotechnology Journal 3(3): 325–338.

Nadeau JH (2003) Modifier genes and protective alleles in human and mice. Current Opinion in Genetics & Development 13(3): 290–295.

Van Ham TJ, Breitling R, Swertz MA et al. (2009) Neurodegenerative diseases: lessons from genome‐wide screens in small model organisms. EMBO Molecular Medicine 1(8–9): 360–370.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Kearney, Jennifer A, and Jorge, Benjamin S(Apr 2012) Genetic Modifiers of Neurological Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023856]