genetic research designs in the real world l.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Genetic research designs in the real world PowerPoint Presentation
Download Presentation
Genetic research designs in the real world

Loading in 2 Seconds...

play fullscreen
1 / 28

Genetic research designs in the real world - PowerPoint PPT Presentation


  • 282 Views
  • Uploaded on

Genetic research designs in the real world Vishwajit L Nimgaonkar MD, PhD University of Pittsburgh nimga@pitt.edu Complex disorders: models of causation Genetic factors : Several genes induce cumulative, small but discrete effects +

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Genetic research designs in the real world' - niveditha


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
genetic research designs in the real world

Genetic research designs in the real world

Vishwajit L Nimgaonkar MD, PhD

University of Pittsburgh

nimga@pitt.edu

complex disorders models of causation
Complex disorders: models of causation

Genetic factors: Several genes induce cumulative, small but discrete effects

+

Environmental factors: etiological role / increased variability

-No Etiological Factor Necessary or Sufficient

-Formal proof dependent on statistical analyses

factors influencing mapping efforts
Factors influencing mapping efforts
  • What is the phenotype?
  • What polymorphisms are being used?
  • What is the study design?
key phenotype issues
Key phenotype issues
  • Is the phenotype heritable?
    • Proportion of risk due to genetic factors?
    • Proportion of risk due to an individual gene (# genes?)
  • Familial aggregation does not necessarily prove genetic etiology
  • Can the phenotype be evaluated reliably?
slide5

Discrete

Continuous

(disease)

(liability)

0

1

t

What is the phenotype?

(L Almasy, PhD)

phenotypes
Phenotypes
  • Qualitative (diagnostic status)
    • Clinically relevant
    • Difficulties in delineating ‘genetic’ phenotype
  • Quantitative (‘endophenotype’)
    • Heritable
    • Differences between cases and controls
    • Differences between unaffected relatives & controls
    • Plausible role in pathogenesis, proximate to Dx
what polymorphisms
What polymorphisms?
  • Single nucleotide polymorphisms: SNPs
  • Repeat polymorphisms
  • Insertions / deletions
gene mapping studies concepts
Gene mapping studies: concepts
  • Examine correlation between genetic variation and trait of interest
  • Significant correlation establishes genetic etiology
slide10

Human genome: 3 billion base pairs

(estimated variations = 8,000,000 – 10,000,000)

Problems

1. All genetic variations unknown

2. All variants can not be evaluated

slide12

*Mutation*

Haplotype 1

Marker A1

Marker A2

Marker B1

Marker B2

Gene mapping concepts

case

control

slide13

Transmission Of

Normal Gene

Generations:

1

2

Ill Individual

Healthy Individual

3

Transmission Of

Disease Gene

n

Recombination based gene mapping

linkage association

founder

generations

Linkage

Association

Linkage / Association

what is the study design15
What is the study design?

POSITIONAL CLONING

Step 1: Identify large shared

chromosomal segments

among cases within families

(LINKAGE)

Step 2: Narrow the shared region

using cases and controls (ASSOCIATION).

related issues
Related issues
  • Ascertainment and recruitment!
  • Power: more is better! ‘much, much more’ preferred
  • Design modification
    • Two stage design (accept lower lod cutoffs)
    • Covariate based analyses
linkage affected sib pairs identity by descent

A,B

A,C

A,B

A,B

A,B

C,D

Linkage: affected sib-pairs (identity by descent)

Alleles shared IBD:

2

0

1

0.25

Prevalence:

0.50

0.25

asp analysis
ASP analysis
  • Convenient design
  • Concerns
    • Truncation of family size due to morbidity
    • ‘True’ sibling recurrence risk
    • Uncertain paternity
    • Twinning
  • Power: n = 400 ASPs; power > 80% for λs = 3.0 (LOD = 3)
quantitative trait mapping
Quantitative trait mapping
  • Quantitative trait analyses
    • Standard variance component analyses
    • Multipoint analyses
    • Sequential search strategies
    • Epistasis
    • Multivariate analyses
    • Bivariate analyses with diagnosis + trait
slide22

Transmission Of

Normal Gene

Generations:

1

2

Ill Individual

Healthy Individual

3

Transmission Of

Disease Gene

n

Associations at the population-level

factors influencing associations
Factors influencing associations
  • Sample selection & size
  • Population history (fitness, drift, migration)
  • Features of mutations (no, age, frequency)
  • Features of markers (informativeness, LD)
  • Number of comparisons
  • Ethnic admixture
transmission disequilibrium test tdt
Transmission Disequilibrium Test (TDT)

A1, A2

A3, A4

A4, A3

A1, A1

A2, A2

A2, A1

A1, A2

A1, A4

A1, A3

Reject

Accept

Accept

family based associations
Family based associations
  • Recruitment expensive
  • Ascertainment may be biased
  • Easier than multiplex pedigrees
  • Power: Issues
    • Uncertain paternity
    • Genotyping errors
    • Power diminishes for case-parent duos
novel designs
‘Novel’ designs
  • Cytogenetic abnormalities
  • Pooled DNA analyses
thank you
Thank you!!
  • Collaborators:
    • Laura Almasy, PhD
    • Bernie Devlin, PhD
    • Rodeny Go, PhD
    • Ruben Gur, PhD
    • Raquel Gur, MD, PhD