Parental genotypes in the risk of a complex disease.

Our understanding of the genetic etiology of complex disorders is still elusive. According to the common-variant/common-disease hypothesis, frequent functional polymorphisms are the best candidates for disease-susceptibility alleles. Implicitly, we also assume that disease-susceptibility alleles are preferentially transmitted from parents to the affected offspring and that this effect can be captured by the transmission/disequilibrium test (TDT). However, our study of genetic predisposition to childhood acute lymphoblastic leukemia suggests that a focus on the patient's genotype might, in certain instances, be misleading. Our results indicate that, at least at some loci, parental genetics might be of primary importance in predicting the risk of cancer in this pediatric model of a complex disease. Consequently, in addition to TDT, other complementary strategies will need to be simultaneously applied to dissect genetic predisposition to complex disorders.

[1]  Joseph D. Terwilliger,et al.  Gene Mapping in the 20th and 21st Centuries: Statistical Methods, Data Analysis, and Experimental Design , 2009, Human biology.

[2]  C. Weinberg,et al.  Regarding "parental genotypes in the risk of a complex disease". , 2002, American journal of human genetics.

[3]  P. Kraft,et al.  Family-based association tests incorporating parental genotypes. , 2002, American journal of human genetics.

[4]  K. Lunetta,et al.  Testing for population subdivision and association in four case-control studies. , 2002, American journal of human genetics.

[5]  E. Génin,et al.  Absence of association of thrombophilia polymorphisms with intrauterine growth restriction. , 2002, The New England journal of medicine.

[6]  D. Labuda,et al.  Childhood Acute Lymphoblastic Leukemia Associated with Parental Alcohol Consumption and Polymorphisms of Carcinogen-Metabolizing Genes , 2002, Epidemiology.

[7]  D. Labuda,et al.  Role of NQO1, MPO and CYP2E1 genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia , 2002, International journal of cancer.

[8]  E. Lander,et al.  On the allelic spectrum of human disease. , 2001, Trends in genetics : TIG.

[9]  K. Godfrey,et al.  Fetal programming and adult health , 2001, Public Health Nutrition.

[10]  H. Mohrenweiser,et al.  Genetic variability in susceptibility and response to toxicants. , 2001, Toxicology letters.

[11]  M Ingelman-Sundberg,et al.  Genetic variability in susceptibility and response to toxicants. , 2001, Toxicology letters.

[12]  Ferguson,et al.  Possible relationship between birth weight and cancer incidence among young adults. , 2000, Annals of epidemiology.

[13]  J. Crow.  The origins, patterns and implications of human spontaneous mutation , 2000, Nature Reviews Genetics.

[14]  Eric S. Lander,et al.  The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes , 2000, Nature Genetics.

[15]  P. Donnelly,et al.  Association mapping in structured populations. , 2000, American journal of human genetics.

[16]  D. Labuda,et al.  Genetic polymorphisms of N-acetyltransferases 1 and 2 and gene-gene interaction in the susceptibility to childhood acute lymphoblastic leukemia. , 2000, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[17]  John M. Lachin,et al.  Biostatistical Methods: The Assessment of Relative Risks , 2000 .

[18]  D. Labuda,et al.  Genetic Susceptibility to Childhood Acute Lymphoblastic Leukemia , 2000, Leukemia & lymphoma.

[19]  D. Sinnett,et al.  Preconceptional paternal exposure to pesticides and increased risk of childhood leukaemia , 1999, The Lancet.

[20]  D. Labuda,et al.  Risk of childhood leukemia associated with exposure to pesticides and with gene polymorphisms. , 1999, Epidemiology.

[21]  R. Elston.  Approaches to Gene Mapping in Complex Human Diseases. Edited by Jonathan L. Haines and Margaret A. Pericak Vance. John Wiley and Sons, New York, 1998. p. xxii + 434 pp., $69.95. , 1999 .

[22]  D. Labuda,et al.  Susceptibility to childhood acute lymphoblastic leukemia: influence of CYP1A1, CYP2D6, GSTM1, and GSTT1 genetic polymorphisms. , 1999, Blood.

[23]  J. Seckl,et al.  Intrauterine events and the programming of adulthood disease: the role of fetal glucocorticoid exposure (Review). , 1998, International journal of molecular medicine.

[24]  C R Weinberg,et al.  A log-linear approach to case-parent-triad data: assessing effects of disease genes that act either directly or through maternal effects and that may be subject to parental imprinting. , 1998, American journal of human genetics.

[25]  F P Perera,et al.  Environment and cancer: who are susceptible? , 1997, Science.

[26]  C. J. Chen,et al.  Genetic polymorphisms of CYP2E1, GSTM1, and GSTT1; environmental factors and risk of oral cancer. , 1997, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[27]  E. Bowman,et al.  A cytochrome P4502E1 genetic polymorphism and tobacco smoking in breast cancer , 1996, Molecular carcinogenesis.

[28]  N Risch,et al.  The Future of Genetic Studies of Complex Human Diseases , 1996, Science.

[29]  K. Kawajiri,et al.  Different regulation and expression of the human CYP2E1 gene due to the RsaI polymorphism in the 5'-flanking region. , 1994, Journal of biochemistry.

[30]  Pieter H. Reitsma,et al.  Mutation in blood coagulation factor V associated with resistance to activated protein C , 1994, Nature.

[31]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[32]  W. Ewens,et al.  Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). , 1993, American journal of human genetics.

[33]  R. Lande,et al.  Genetic correlations and maternal effect coefficients obtained from offspring-parent regression. , 1989, Genetics.

[34]  C. Falk,et al.  Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations , 1987, Annals of human genetics.

[35]  E S Lander,et al.  The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. , 2000, Nature genetics.

[36]  A. Chakravarti.  Population genetics—making sense out of sequence , 1999, Nature Genetics.

[37]  E. Lander,et al.  Characterization of single-nucleotide polymorphisms in coding regions of human genes , 1999 .

[38]  A. Lechasseur.  Serge COURVILLE (dir.), Atlas historique du Québec : population et territoireSerge COURVILLE (dir.), Atlas historique du Québec : population et territoire , 1999 .

[39]  A. Ekbom,et al.  Growing evidence that several human cancers may originate in utero. , 1998, Seminars in cancer biology.

[40]  B Müller-Myhsok,et al.  Genetic analysis of complex diseases. , 1997, Science.

[41]  O. Mayo.  Genetic analysis of a complex disease. , 1994, Alcohol and alcoholism (Oxford, Oxfordshire). Supplement.

[42]  S. Sheps,et al.  Sample size and power. , 1993, Journal of investigative surgery : the official journal of the Academy of Surgical Research.