- Family-based study
- Missing data
- Maternal-fetal genotype incompatibility
Genes can be associated with disease through an individual’s inherited genotype, the maternal genotype or the interaction between these two. When the gene is highly polymorphic, it is more difficult to identify the gene’s functional role than for less polymorphic loci, because different alleles at the locus may be associated with the disease through separate and joint effects from maternal and offspring genotypes. Family-based studies are used to test genetic associations because of their robustness to population stratification. However, parental genotype data are often missing, and omitting incompletely genotyped families is inefficient. Methods have been proposed to accommodate incomplete families in family-based association studies. They are not easily generalized to allow simultaneous examination of offspring allelic, maternal allelic and maternal-fetal genotype (MFG) incompatibility effects. Since many MFG incompatibility effects occur through matching between maternal and offspring’s genotypes, we present an identity-by-state (IBS) framework to incorporate incomplete families in the MFG test when modeling genetic effects produced by a polymorphic gene. Using simulations, we examine the MFG test’s performance with incomplete parental genotype data and an IBS framework. The MFG test using the IBS framework is immune to population stratification and efficiently uses information from incomplete families.
Copyright © 2006 S. Karger AG, Basel
- Dyment DA, Ebers GC, Sadovnick AD: Genetics of multiple sclerosis. Lancet Neurol 2004;3:104–110.
- Dyment DA, Herrera BM, Cader MZ, Willer CJ, Lincoln MR, Sadovnick AD, Risch N, Ebers GC: Complex interactions among MHC haplotypes in multiple sclerosis. Hum Mol Genet 2005;14:2019–2026.
- Sinsheimer JS, Palmer CGS, Woodward JA: Detecting genotype combinations that increase risk for disease: The maternal-fetal genotype incompatibility test. Genetic Epidemiology 2003;24:1–13.
- Stubbs EG, Ritvo ER, Mason-Brothers A: Autism and shared parental HLA antigens. J Am Acad Child Psychiatry 1985;24:182–185.
- Palmer CSG, Hsieh H-J, Reed EF, Lonnqvist J, Peltonen L, Woodward JA, Sinsheimer JS: HLA-B maternal-fetal genotype matching increases risk of schizophrenia. Am J Hum Genet 2006;79:710–715.
- Stevens AM, Tsao BP, Hahn BH, Guthrie K, Lambert NC, Porter AJ, Tylee TS, Nelson JL: Maternal HLA class II compatibility in men with systemic lupus erythematosus. Arthritis Rheum 2005;52:2768–2773.
- Willer CJ, Dyment DA, Sadovnick AD, Ebers GC: Maternal–offspring HLA-DRB1 compatibility in multiple sclerosis. Tissue Antigens 2005;66:44–47.
- Curtis D, Sham PC: A note on the application of the transmission disequilibrium test when a parent is missing. Am J Hum Genet 1995;56:811–812.
- Clayton D: A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am J Hum Genet 1999;65:1170–1177.
- Rabinowitz D, Laird N: A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 2000;50:211–223.
- Rabinowitz D: Adjusting for population heterogeneity and misspecified haplotype frequencies when testing nonparametric null hypotheses in statistical genetics. Journal of the American Statistical Association 2002;97:742–758.
- Chen YH: New approach to association testing in case-parent designs under informative parental missingness. Genet Epidemiol 2004;27:131–140.
- Palmer CGS, Turunen JA, Sinsheimer JS, Minassian M, Paunio T, Lonnqvist J, Peltonen L, Woodward JA: RHD maternal-fetal genotype incompatibility increases schizophrenia susceptibility. American Journal of Human Genetics 2002;71:1312–1319.
- Schaid DJ: Adjusting for population heterogeneity and misspecified haplotype frequencies when testing nonparametric null hypotheses in statistical genetics – Comment. Journal of the American Statistical Association 2002;97:754–756.
- Weinberg CR: Allowing for missing parents in genetic studies of case-parent triads. Am J Hum Genet 1999;64:1186–1193.
- Minassian SL, Palmer CGS, Turunen JA, Paunio T, Lonnqvist J, Peltonen L, Woodward AJ, Sinsheimer JS: Incorporating serotypes into family based association studies using the MFG test. Annals of Human Genetics 2006, in press.
- Lange K: SEARCH. Department of Biomathematics, University of California, Los Angeles: Los Angeles, 1991.
- Beydoun H, Saftlas AF: Association of human leukocyte antigen sharing with recurrent spontaneous abortions. Tissue Antigens 2005;65:123–135.
- Ober C, Hyslop T, Elias S, Weitkamp LR, Hauck W: Human leukocyte antigen matching and fetal loss: Results of a 10 year prospective study. Human Reproduction 1998;13:33–38.
- Kraft P, Palmer CGS, Woodward JA, Turunen JA, Minassian M, Paunio T, Lonnqvist J, Peltonen L, Sinsheimer JS: RHD Maternal-Fetal genotype incompatibility and schizophrenia: Extending the MFG test to include multiple siblings and birth order. European Journal of Human Genetics 2004;12:192–198.
- Hsieh H, Palmer CGS, Harney S, Newton JL, Wordsworth P, Brown MA, Sinsheimer JS: The v-MFG test: Investigating maternal, offspring, and maternal-fetal genetic incompatibilities effects on disease and viability. Genet Epidemiol 2006;30:333–347.
- Little RJA, Rubin D, Statistical analysis with missing data. 2nd ed. 2002, Hoboken: Wiley-Interscience.
- Ferguson TS: A Course in Large Sample Theory. 1996:Chapman & Hall/CRC.
- Kraft P, Hsieh HJ, Cordell HJ, Sinsheimer J: A conditional-on-exchangeable-parental-genotypes likelihood that remains unbiased at the causal locus under multiple-affected-sibling ascertainment. Genet Epidemiol 2005;29:87–90.
- Allen A, Rathouz P, Satten GA: Informative missingness in genetic association studies: Case-parent designs. American Journal of Human Genetics 2003;72:671–680.
- Clayton D, Chapman J, Cooper J: Use of unphased multilocus genotype data in indirect association studies. Genet Epidemiol 2004;27:415–428.
- Li W, Gregersen PK: Reconstructing Haplotypes in Pedigrees: Importance of Parental Information. American Journal of Medical Genetics 2004;124A:107–109.
- Kuhn L, Abrams EJ, Palumbo P, Bulterys M, Aga R, Louie L, Hodge T: Maternal versus paternal inheritance of HLA class I alleles among HIV-infected children: consequences for clinical disease progression. Aids 2004;18:1281–1289.
Dr. Janet Sinsheimer
Department of Human Genetics, 5357C Gonda Center
695 Charles E. Young Drive South, Box 957088
Los Angeles, CA 90095-7088 (USA)
Tel. +1 310 825 8002, Fax +1 310 825 8685, E-Mail email@example.com
Received: April 3, 2006
Accepted after revision: August 7, 2006
Published online: October 25, 2006
Number of Print Pages : 10
Number of Figures : 2, Number of Tables : 3, Number of References : 28
Human Heredity (International Journal of Human and Medical Genetics)
Vol. 62, No. 3, Year 2006 (Cover Date: November 2006)
Journal Editor: Devoto, M. (Philadelphia, Pa.)
ISSN: 0001–5652 (print), 1423–0062 (Online)
For additional information: http://www.karger.com/HHE
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