Association Testing in Related Individuals

Family data is correlated that could lead to inflation in test statistics if not accounted for. Many genetic studies contain related individuals. Family-based studies were developed to avoid bias due to population structure; Biological family members are genetically matched.

Most behavioral and environmental factors do not alter DNA, so SNP associations are unlikely to be confounded EXCEPT confounding by ancestry.

Population Stratification Bias

• For case control studies, population structure means bad matching; cases and controls come from different genetic populations.
• For cohort/cross-sectional studies with quantitative phenotypes, if the phenotype and genotype distributions both differ by population then population stratification bias can occur.
• If a population consists of a mixture of subpopulations and it is not accounted for in the analysis, false evidence for association may result.
• Spurious association only occurs when there is a difference in BOTH genotype and phenotype distribution with subpopulations.

Designs for Family-Based Studies

• Early-onset phenotypes:
  • Case-parent trios (where child is effected) - Transmission disequilibrium test (TDT)
• Late-onset phenotypes:
  • Discordant siblings - sub-TDT/conditional logistic regression
• General designs
  • Nuclear or extended families - Family-based association test (FBAT)

Case-Parent Trios

In this design we collect samples of trios; Two parents and one affected child (affection status of parents are not considered). The idea is under Mendels laws, heterozygous parents transmit each allele with equal probability (1/2) regardless of population structure. If there is preferential transmission of a specific allele from parents to affected offspring it indicates that allele is associated with the disease.

Transmission Disequilibrium Test (TDT)

Tests whether a particular marker allele is transmitted to affected offspring more frequently than expected. Non-transmitted alleles act as matched controls.

H₀: No association or no linkage
H_a: Variant is associated with disease/trait (and is not due to population structure)

Notation:

• a = number of AA parents
• b + c = number of AB parents
  • b = Number of AB parents transmitting B to affected child
  • c = Number of AB parents transmitting C to affected child
• d = number of BB parents

Under the null we would expect:

The test statistic follows a McNemar test:

We observe this is only a function of the heterozyzgous parents, homozygous parents provide no information.