Distinguishing the effects of maternal and offspring genes through studies of "case-parent triads".
A gene variant that increases disease risk will be overrepresented among diseased persons, even compared with their own biologic parents. This insight has led to tests based solely on the asymmetric distribution of a variant allele among cases and their parents (e.g., the transmission/disequilibrium test). Existing methods focus on effects of alleles that operate through the offspring genotype. Alleles can also operate through the mother's genotype, particularly for conditions such as birth defects that have their origins in fetal life. An allele working through the mother would have higher frequency in case-mothers than in case-fathers. The authors develop a log-linear method for estimating relative risks for alleles in the context of case-parent triads. This method is able to detect the effects of genes working through the offspring, the mother, or both. The authors assume Mendelian inheritance, but Hardy-Weinberg equilibrium is unnecessary. Their approach uses standard software, and simulations demonstrate satisfactory power and confidence interval coverage. This method is valid with a self-selected or hospital-based series of cases and helps to protect against misleading inference that can result when cases and controls are randomly sampled from a population not in Hardy-Weinberg equilibrium.
Wilcox
A J
AJ
Epidemiology Branch, NIEHS, Research Triangle Park, NC 27709, USA.
Weinberg
C R
CR
Lie
R T
RT
D045103:5,10-Methylenetetrahydrofolate Reductase (FADH2); D000483:Alleles; D016022:Case-Control Studies; D003198:Computer Simulation; D000013:Congenital Abnormalities / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D006801:Humans; D016013:Likelihood Functions; D015810:Linkage Disequilibrium; D008431:Maternal-Fetal Exchange / Q000235:genetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D010088:Oxidoreductases / Q000235:genetics; D011247:Pregnancy; D012307:Risk Factors
D005819:Genetic Markers; D010088:Oxidoreductases; D045103:5,10-Methylenetetrahydrofolate Reductase (FADH2); D042965:Methylenetetrahydrofolate Reductase (NADPH2)