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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?.

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statistical issues in human genetics

Statistical Issuesin Human Genetics

Jonathan L. Haines Ph.D.

Center for Human Genetics Research

Vanderbilt University Medical Center

what can the genes tell us
What Can The Genes Tell Us?
  • Give us a better understanding of the underlying biology of the trait in question
  • Serve as direct targets for better treatments
    • Pharmacogenetics
    • Interventions
  • Give us better predictions of who might develop disease
  • Give us better predictions of the course of the disease
  • Lead to knowledge that can help find a cure or prevention
slide5

Watson and Crick started it all in 1953 with the description of DNA

  • 53 Year Anniversary of the paper will be in April.
  • Both Won Nobel Prize
slide7

The DNA Between Individuals is Identical.

All differences are in the 0.1% of DNA that varies.

A

C

C

G

T

C

C

A

G

G

A

C

C

G

T

G

C

A

G

G

It’s hard to

believe sometimes!

single nucleotide polymorphisms snps one of the most common types of variation
Single-Nucleotide Polymorphisms (SNPs)One of the most common types of variation

GATCCTGTAGCT

< Normal

1st Chromosome

GATCCTCTAGCT

< Disease

2nd Chromosome

G/C

Affected

Normal

GATCCTGTAGCT

GATCCTCTAGCT

GATCCTGTAGCT

GATCCTCTAGCT

Extremely frequent across the genome (~1/400 bp) -> high resolution

Easy to genotype -> high-throughput techniques

slide10

What are We Looking For?

Earth

City

Street

Address

Human Genome

Chromosome

Gene (DNA)

Band

slide11

640 cubic yards

3,000 MB

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)

slide13

Disease Gene Discovery In Complex Disease

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

case-control, family-based

b. Model-independent

sib-pair, relative pair

a. Model-dependent

Lod score

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

classes of human genetic disease
CLASSES OF HUMANGENETIC DISEASE
  • Diseases of Simple Genetic Architecture
    • Can tell how trait is passed in a family: follows a recognizable pattern
    • One gene per family
    • Often called Mendelian disease
    • Usually quite rare in population
    • “Causative” gene
  • Diseases of Complex Genetic Architecture
    • No clear pattern of inheritance
    • Moderate to strong evidence of being inherited
    • Common in population: cancer, heart disease, dementia etc.
    • Involves many genes or genes and environment
    • “Susceptibility” genes
classes of human genetic disease1
CLASSES OF HUMANGENETIC DISEASE
  • Diseases of Simple Genetic Architecture
    • Can tell how trait is passed in a family: follows a recognizable pattern
    • One gene per family
    • Often called Mendelian disease
    • Usually quite rare in population
    • “Causative” gene
  • Diseases of Complex Genetic Architecture
    • No clear pattern of inheritance
    • Moderate to strong evidence of being inherited
    • Common in population: cancer, heart disease, dementia etc.
    • Involves many genes or genes and environment
    • “Susceptibility” genes
modes of inheritance
Modes of Inheritance
  • Autosomal Dominant
    • Huntington disease
  • Autosomal Recessive
    • Cystic fibrosis
  • X-linked
    • Duchenne muscular dystrophy
  • Mitochondrial
    • Leber Optic atrophy
  • Additive
    • HLA-DR in multiple sclerosis
  • Combinations of the above
    • RP (39 loci), Nonsyndromic deafness
linkage analysis
Linkage Analysis
  • Traces the segregation of the trait through a family
  • Traces the segregation of the chromosomes through a family
  • Statistically measures the correlation of the segregation of the trait with the segregation of the chromosome
slide18

A SAMPLE PEDIGREE

The RED chromosome is key

measures of linkage parametric vs non parametric
Measures of LinkageParametric Vs Non-Parametric
  • Two major approaches toward linkage analysis
  • Parametric: Defines a genetic model of the action of the trait locus (loci). This allows more complete use of the available data (inheritance patterns and phenotype information).
    • The historical approach towards linkage analysis. Development driven by need to map simple Mendelian diseases
    • Quite powerful when model is correctly defined
  • Non-Parametric: Uses either a partial genetic model or no genetic model. Relies on estimates of allele/ haplotype/region sharing across relatives. Makes far fewer assumptions about the action of the underlying trait locus(loci).
linkage analysis1
Linkage Analysis
  • Families
    • Affected sibpairs
    • Affected relative pairs
    • Extended families
  • Traits
    • Qualitative (affected or not)
    • Quantitative (ordinal, continuous)
  • There are numerous different methods that can be applied
  • These methods differ dramatically depending on the types of families and traits
recombination nature s way of making new combinations of genetic variants
Recombination: Nature’s way of making new combinations of genetic variants

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.

linkage analysis in humans
Linkage Analysis in Humans
  • Measure the rate of recombination between two or more loci on a chromosome
  • Can be done with any loci, but primary application is to find the location of a trait variant by measuring linkage to known marker variants.
lod score analysis
LOD Score Analysis

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:

L.R. =

: 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

fraction

The LOD score (z) is the log10 (L.R.)

classes of human genetic disease2
CLASSES OF HUMANGENETIC DISEASE
  • Diseases of Simple Genetic Architecture
    • Can tell how trait is passed in a family: follows a recognizable pattern
    • One gene per family
    • Often called Mendelian disease
    • Usually quite rare in population
    • “Causative” gene
  • Diseases of Complex Genetic Architecture
    • No clear pattern of inheritance
    • Moderate to strong evidence of being inherited
    • Common in population: cancer, heart disease, dementia etc.
    • Involves many genes or genes and environment
    • “Susceptibility” genes
slide25

Study Designs

Linkage Analysis

Large Families

Small Families

Association Studies

Family-Based

Case-Control

linkage vs association
Linkage vs. Association

Linkage

Association

Shared within Families

Shared across Families

testing candidate genes
TESTING CANDIDATE GENES

Disease

Normal

5/20

5/20

Gene is not important

testing candidate genes1
TESTING CANDIDATE GENES

Disease

Normal

10/20

5/20

Gene may be important

two basic study designs for association analysis
Case-Control

Advantages

Power

Ascertainment

Disadvantages

Sensitivity to assumptions

Matching

Family-Based

Parent-child Trio

Discordant sibpairs

Advantages

Use existing samples

Robustness to assumptions

Disadvantages

Ascertainment

Power

Two Basic Study Designsfor Association Analysis
methods for family based association studies
Parent-Child

AFBAC

TDT

HHRR

QTDT

Sibpair

S-TDT

DAT

Sibship

SDT

WSDT

FBAT

Pedigree

Transmit

PDT

FBAT

METHODS FOR FAMILY-BASED ASSOCIATION STUDIES
transmission disequilibrium test tdt
TRANSMISSION DISEQUILIBRIUM TEST (TDT)
  • Examines transmission of alleles to affected individuals
  • Requires:
    • Linkage (transmission through meioses); and
    • Association (specific alleles)
  • Test of linkage if association assumed
  • Test of association if linkage assumed
  • Test of linkage AND association if neither assumed
  • Uses the non-transmitted alleles, effectively, as the control group. Can make “pseudocontrol” by creating genotype of the two non-transmitted alleles
  • Requires phenotype only for the child
tdt calculation

1

2

(B-C)2

TDT=

(B+C)

TDT calculation

Transmitted

2

1

12

12

Non-Transmitted

11

With > 5 per cell, this follows

a 2 distribution with 1 df

slide33

TDT

12

12

Transmitted

1 2

Not transmitted 1 0 0

2 2 0

11

slide34

TDT

22

12

Transmitted

1 2

Not transmitted 1 0 0

2 1 1

12

slide35

TDT

22

11

Transmitted

1 2

Not transmitted 1 1 0

2 0 1

12

tdt example

1

1

2

2

(B-C)2

TDT=

(B+C)

TDT Example

Transmitted

Transmitted

2

2

1

1

Non-Transmitted

Non-Transmitted

(42-25)2

= 4.31

TDT=

(42+25)

two basic study designs for association analysis1
Case-Control

Advantages

Power

Ascertainment

Disadvantages

Sensitivity to assumptions

Matching

Family-Based

Parent-child Trio

Discordant sibpairs

Advantages

Use existing samples

Robustness to assumptions

Disadvantages

Ascertainment

Power

Two Basic Study Designsfor Association Analysis
analysis of case control data
Analysis of Case-Control Data
  • Standard epidemiological approaches can be used
  • Qualitative trait
    • Logistic regression
  • Quantitative trait
    • Linear regression
  • The usual concerns about matching but must also worry about false-positives from population substructure
incorporating genetics into your studies
Incorporating Geneticsinto Your Studies
  • Obtain appropriate IRB approval
    • DNA studies are quite common
    • Template language exists for IRB approval and consent forms
    • Genetic Studies Ascertainment Core (GSAC) can help
    • Kelly Taylor: ktaylor@chgr.mc.vanderbilt.edu
  • Collect family history information
  • Obtain DNA sample
    • Venipuncture
    • Buccal wash/swab
    • Finger stick
  • Extract/Store DNA
    • DNA Resources Core can help
    • Cara Sutcliffe: cara@chgr.mc.vanderbilt.edu
  • http://chgr.mc.vanderbilt.edu/
what can the genes tell us1
What Can The Genes Tell Us?
  • Give us a better understanding of the underlying biology of the trait in question
  • Serve as direct targets for better treatments
    • Pharmacogenetics
    • Interventions
  • Give us better predictions of who might develop disease
  • Give us better predictions of the course of the disease
  • Lead to knowledge that can help find a cure or prevention