Statistical Issues in Human Genetics. Jonathan L. Haines Ph.D. Center for Human Genetics Research Vanderbilt University Medical Center. Complex Disease. COMMON COMPLEX DISEASE. Environment. Genes. Complex Disease. COMMON COMPLEX DISEASE. Environment. Genes. What Can The Genes Tell Us?.
Jonathan L. Haines Ph.D.
Center for Human Genetics Research
Vanderbilt University Medical Center
All differences are in the 0.1% of DNA that varies.
It’s hard to
Extremely frequent across the genome (~1/400 bp) -> high resolution
Easy to genotype -> high-throughput techniques
1/100 cubic inch
1 x 10-6 MB
It really is like finding a needle in a haystack!
(and a very BIG haystack, at that)
1. Define Phenotype
a. Consistency b. Accuracy
2. Define the Genetic Component
a. Twin Studies b. Adoption Studies c. Family Studies d. Heritability e. Segregation Analysis
3. Define Experimental Design
4. Ascertain Families
a. Case-Control b. Singleton c. Sib Pairs d. Affected Relative Pairs
5. Collect Data
a. Family Histories b. Clinical Results c. Risk Factors d. DNA Samples
6. Perform Genotype Generation
a. Genomic Screen b. Candidate Gene
7. Analyze data
c. Association studies
sib-pair, relative pair
8. Identify, Test, and Localize Regions of Interest
9. Bioinformatics and Gene Identification
10. Identify Susceptibility Variation(s)
11. Define Interactions
a. Gene-Gene b. Gene-Environment
The RED chromosome is key
A. B. C. D.
A. A diploid cell.
B. DNA replication and pairing of homologous chromosomes to form bivalent.
C. Chiasma are formed between the chromatids of homologous chromosomes
D. Recombination is complete by the end of prophase I.
The likelihood ratio as defined by Morton (1955):
L(pedigree| = x)
L(pedigree | = 0.50)
where represents the recombination fraction and where 0 x 0.49.
When all meioses are “scorable”, the LR is constructed as:
: z() is the lod score at a particular value
of the recombination fraction
: z() is the maximum lod score, which
occurs at the MLE of the recombination
The LOD score (z) is the log10 (L.R.)
Shared within Families
Shared across Families
Gene is not important
Gene may be important
Not transmitted 1 0 0
2 2 0
Not transmitted 1 0 0
2 1 1
Not transmitted 1 1 0
2 0 1