title: Mixed effects models for quantitative trait loci mapping with inbred strains.
abstract: Fixed effects models have dominated the statistical analysis of genetic crosses between inbred strains. In spite of their popularity, the traditional models ignore polygenic background and must be tailored to each specific cross. We reexamine the role of random effect models in gene mapping with inbred strains. The biggest difficulty in implementing random effect models is the lack of a coherent way of calculating trait covariances between relatives. The standard model for outbred populations is based on premises of genetic equilibrium that simply do not apply to crosses between inbred strains since every animal in a strain is genetically identical and completely homozygous. We fill this theoretical gap by introducing novel combinatorial entities called strain coefficients. With an appropriate theory, it is possible to reformulate QTL mapping and QTL association analysis as an application of mixed models involving both fixed and random effects. After developing this theory, our first example compares the mixed effects model to a standard fixed effects model using simulated advanced intercross line (AIL) data. Our second example deals with hormone data. Here multivariate traits and parameter identifiability questions arise. Our final example involves random mating among eight strains and vividly demonstrates the versatility of our models.
authors.affiliation: Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas 78245-0549, USA. lbauman@sfbrgenetics.org
authors.forename: Lara E
authors.initials: LE
authors.lastname: Bauman
authors.forename: Janet S
authors.initials: JS
authors.lastname: Sinsheimer
authors.forename: Eric M
authors.initials: EM
authors.lastname: Sobel
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lange
mesh_terms: D000818:Animals; D001947:Breeding; D002874:Chromosome Mapping; D019295:Computational Biology; D003198:Computer Simulation; D003433:Crosses, Genetic; D005260:Female; D008297:Male; D051379:Mice; D008954:Models, Biological; D015233:Models, Statistical; D010641:Phenotype; D040641:Quantitative Trait Loci
references.citation: Genet Epidemiol. 2005 Jul;29(1):36-50
references.pmid: 15834862
references.citation: Genetics. 2001 Sep;159(1):371-87
references.pmid: 11560912
references.citation: Nat Rev Genet. 2005 Apr;6(4):271-86
references.pmid: 15803197
references.citation: Ann Hum Genet. 1982 Oct;46(4):373-83
references.pmid: 6961886
references.citation: Am J Hum Genet. 2000 Mar;66(3):1153-7
references.pmid: 10712227
references.citation: Hum Biol. 1993 Dec;65(6):941-66
references.pmid: 8300087
references.citation: Genetics. 2005 Mar;169(3):1699-709
references.pmid: 15654110
references.citation: Theor Appl Genet. 1990 Jul;80(1):11-6
references.pmid: 24220804
references.citation: Am J Med Genet. 1986 Jul;24(3):483-91
references.pmid: 3728567
references.citation: Genet Epidemiol. 1997;14(6):1053-8
references.pmid: 9433623
references.citation: Twin Res. 2002 Dec;5(6):572-6
references.pmid: 12573188
references.citation: Ann Hum Genet. 2005 Sep;69(Pt 5):590-611
references.pmid: 16138917
references.citation: Genetics. 2000 Oct;156(2):913-22
references.pmid: 11014836
references.citation: Bioinformatics. 2002 Feb;18(2):339-40
references.pmid: 11847090
references.citation: Genetics. 1999 Jul;152(3):1203-16
references.pmid: 10388834
references.citation: Mamm Genome. 1999 Apr;10(4):327-34
references.pmid: 10087288
references.citation: Hum Hered. 2001;51(3):133-44
references.pmid: 11173964
references.citation: Genetics. 1995 Nov;141(3):1199-207
references.pmid: 8582624
references.citation: Am J Hum Genet. 1994 Mar;54(3):535-43
references.pmid: 8116623
references.citation: Genetics. 1989 Jan;121(1):185-99
references.pmid: 2563713
references.citation: Bioinformatics. 2003 May 1;19(7):889-90
references.pmid: 12724300
references.citation: Ann Hum Genet. 1985 Oct;49(4):315-28
references.pmid: 4073838
references.citation: Genetics. 2001 Jan;157(1):445-54
references.pmid: 11139524
references.citation: Genet Epidemiol. 1997;14(6):959-64
references.pmid: 9433607
references.citation: Philos Trans R Soc Lond B Biol Sci. 2005 Jul 29;360(1459):1443-55
references.pmid: 16048787
references.citation: Genetics. 2007 Jan;175(1):321-33
references.pmid: 17028314
references.citation: Am J Hum Genet. 1993 Dec;53(6):1306-19
references.pmid: 8250047
references.citation: Genetics. 1998 Mar;148(3):1373-88
references.pmid: 9539450
references.citation: Genetics. 2005 Sep;171(1):365-76
references.pmid: 15965257
references.citation: Am J Med Genet. 1983 Mar;14(3):513-24
references.pmid: 6859102
references.citation: Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):10972-6
references.pmid: 8248199
references.citation: Am J Hum Genet. 1996 Jun;58(6):1323-37
references.pmid: 8651310
references.citation: Genetics. 1998 Jun;149(2):1139-46
references.pmid: 9611221
references.citation: Genetics. 1999 Oct;153(2):825-35
references.pmid: 10610347
references.citation: Genetics. 1994 Nov;138(3):963-71
references.pmid: 7851788
references.citation: Genes Brain Behav. 2002 Nov;1(4):214-22
references.pmid: 12882366
references.citation: Behav Brain Res. 2001 Nov 1;125(1-2):279-84
references.pmid: 11682119
references.citation: Genet Res. 2000 Jun;75(3):345-55
references.pmid: 10893870
references.citation: Am J Hum Genet. 1999 Aug;65(2):531-44
references.pmid: 10417295
references.citation: Am J Hum Genet. 1990 Dec;47(6):957-67
references.pmid: 2239972
references.citation: Twin Res. 2002 Dec;5(6):554-71
references.pmid: 12573187
references.citation: Biometrics. 2002 Mar;58(1):157-62
references.pmid: 11890311
references.citation: Am J Hum Genet. 1996 Jun;58(6):1347-63
references.pmid: 8651312
references.citation: Genet Epidemiol. 2000;19 Suppl 1:S8-14
references.pmid: 11055364
references.citation: PLoS Biol. 2004 Dec;2(12):e393
references.pmid: 15534693
references.citation: Genetics. 2006 Mar;172(3):1783-97
references.pmid: 16361245
references.citation: Heredity (Edinb). 1992 Oct;69(4):315-24
references.pmid: 16718932
references.citation: Genetics. 2004 Aug;167(4):2055-65
references.pmid: 15342540
references.citation: Am J Med Genet. 1984 Jul;18(3):435-48
references.pmid: 6476005
references.citation: BMC Genet. 2005 Dec 30;6 Suppl 1:S57
references.pmid: 16451669
references.citation: Biostatistics. 2007 Apr;8(2):414-32
references.pmid: 16928955
references.citation: Physiol Genomics. 2003 Sep 29;15(1):44-51
references.pmid: 12865502
references.citation: Genetics. 1994 Apr;136(4):1457-68
references.pmid: 8013918
references.citation: Genet Epidemiol. 2000;19 Suppl 1:S22-8
references.pmid: 11055366
references.citation: Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12649-54
references.pmid: 11050180
references.citation: Theor Appl Genet. 1993 Sep;86(8):1014-22
references.pmid: 24194011