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Genetics in Clinical Research . Jonathan L. Haines, Ph.D. Center for Human Genetics Research 7/16/04. CLASSES OF HUMAN GENETIC DISEASE. Diseases of Simple Genetic Architecture Can tell how trait is passed in a family: follows a recognizable pattern One gene per family

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Genetics in clinical research l.jpg

Genetics in Clinical Research

Jonathan L. Haines, Ph.D.

Center for Human Genetics Research


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  • 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

    • “Causative” gene

  • Diseases of Complex Genetic Architecture

    • No clear pattern of inheritance

    • Moderate to strong evidence of being inherited

    • May be:

      • common in population: dementia, stroke, tremor, etc.

      • Rare in population: Adverse drug response, primary lateral sclerosis, etc.

    • Involves many genes or genes and environment

    • “Susceptibility” genes

    • This is your trait!

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Complex Disease










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Why Test the Genes?

  • Basic Science: Better understanding of biology of disease

    • Direct probe into functional pathways

    • Target for detecting interacting factors

    • Better definition of disease

  • Clinical Science: Making this knowledge useful

    • Improved diagnostic testing

    • Presymptomatic testing

    • Improved prognostic testing

    • Improved treatment (e.g. pharmacogenetics)

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Why test the Genes?Practical reasons

  • Can help make sense of results

    • If there is a lot of variability, it may be due to genetics

    • Can clean up the analysis and find significant results!

    • Can add a sexy new component to your study

    • It can be easy and cheap through the GCRC!

  • Virtually all GCRC studies have a potential genetic component

  • Pilot data can lead to larger funded studies

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  • Broad Search (Genomic screen)

    • Examine a large but representative subset of all genomic variations. Not hindered by poor assumptions of biology.

    • Use families with more than one affected individual.

    • Problem: Lots of genes at the same location!

  • Targeted Search (Candidate genes)

    • Examine a specific and small set of candidate variations based on what we know about the biology of the disease.

    • Can use both families with multiple affected individuals and families with only one affected individual.

    • Problem: There are 50,000 genes and we know very little about their function!

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Physical map: genome sequence

multiple different species

Genetic map: recombination

Linkage disequilibrium map: HapMap

Variation maps





Homology maps

Hardware Technology



Software Technology

Public databases

Analysis programs

Increased productivity

Experiments now possible that were considered impossible just 2 years ago

Genome Toolbox

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Study Designs

Study Designs

Linkage Analysis

Large Families

Small Families

Association Studies



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Association Study Designs

  • Family-based analysis

    • Two flavors

      • Trio (patient and both parents)

      • Discordant sibpairs

    • Multiple statistical methods for analysis

    • Advantage: inherent control for genetic background

    • Disadvantage: family-based

  • Case-Control

    • Standard epidemiological design

    • Statistical methods

      • logistic or linear regression

      • Statistical genetics methods

  • Case only

    • Outcomes analysis

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Genetic Association Analysis

  • Can incorporate gene/gene interactions

    • Look at two or more genes at a time

      • Logistic regression

      • MDR

  • Can incorporate gene/environment interactions

    • Logistic regression

    • MDR

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Need To Characterize The Gene

  • Use genome databases to get known information

    • Gene location (NCBI, Ensembl, Celera)

    • Gene structure (NCBI, Ensembl, Celera)

    • Possible gene functions (OMIM, NCBI, KEGG)

    • Gene expression (tissue localization) (NCBI)

    • Gene variation (HapMap, dbSNP, Celera, OMIM)

      • Deletions

      • Mutations

      • SNPs

      • LD relationships

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Gene Characterization

  • Choose what variants to examine

  • Decide if further polymorphism discovery is needed

  • Many factors to be considered:

    • Frequency of variant

    • Genotyping platform and assay development

    • LD relationships

    • Availability and quality of DNA

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Essential Problem in Choosing the Gene(s) to Study

  • How do we integrate all the available information that we and others generate?

  • How do we locate the one or few genetic variations involved in our trait in the sea of hundreds or thousands of possible variations?

  • Most methods identify a set, often a large set, of possible variations.

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Genomic Convergence




Genomic convergence identifies the intersection of genes found through multiple methods such as drug metabolism, allelic association analysis, and gene expression studies.

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Using Your Time and Effort Wisely

  • Design your study. Genetics can be added easily and will only benefit, not hinder, the main study

  • Do not waste time on the details! We have the expertise to help make it happen.

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Family Ascertainment Core

1207 17th Ave S., Suite 100

Kelly Taylor, MS; Manager

DNA Resources Core

518 Light Hall

Cara Sutcliffe, MS; Manager

Genetic Data Analysis Core

511-515 Light Hall

Chun Li, Ph.D.; Faculty Advisor

Computing/ Bioinformatics Core

515-519 Light Hall

Janey Wang, MS2; Manager

Core Services(

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Family Ascertainment CoreFaculty advisor: Jeff Canter

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Family Ascertainment Core Services

  • IRB and Protocol Development

  • Patient/Family Ascertainment

    • Identify and recruit participants

      • Clinic, local, distant

    • Data collection

      • Family history, clinical, demographic

    • Biological sample collection

      • Phlebotomy

      • Buccal washes

      • Finger sticks

  • Project and Data Management

    • Progeny pedigree and ascertainment database

    • PEDIGENE clinical and genetic database

    • Template forms

      • IRB

      • Family History

      • Clinical

    • Limited access, locked file room

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DNA Resources CoreFaculty Advisor: Doug Mortlock

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DNA extraction


Buccal (wash, brush)

Cell Pellets

Sample tracking and storage

Web-based Oracle database

PI-controlled access

Bar-coded, standardized storage in locked cold room

DNA quantitation

Initiation of lymphoblast cell lines

Microsatellite genotyping

SNP genotyping

Storage of cell lines (LN2 freezers)

DNA Resources CoreServices

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DNA Resources CoreResources

  • 4 Staff

  • Automated DNA large and small volume extraction (Autopure)

  • Locked cold room, liquid nitrogen freezers

  • Bar-coding, RPIDs, web-based database

  • Hitachi FMBIO II laser scanner (fluorescent dyes)

  • ABI 7900HT (high-throughput SNP genotyping)

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Genetic Data Analysis CoreFaculty Advisor: Chun Li

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Linkage Analysis

Parametric lod scores Non-parametric scores

Two disease loci

Linkage Disequilibrium Analysis


Family-based (TDT, S-TDT, PDT)

Gene-Gene Interactions

Gene-Environment Interactions

Logistic Regressions

MDR analysis

Quantitative Trait Locus Analysis

Marker reference maps

Error detection

Mendelian checks

Haplotype checking

Pedigree relationship checking

Consultation on study design

Training on use of software

Data Management

Genetic Data Analysis CoreServices

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7 Staff

PEDIGENE database


Family history


Latest genetic analysis software

Testing of new programs and methods

Experience with strengths and weaknesses

Access to

7 PCs

6 Unix

12 Linux systems


Genetic Data Analysis CoreResources

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Computing/Bioinformatics CoreFaculty advisor: Marylyn Ritchie

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Complete database services

Support of PEDIGENE

Data collection

Web-based data entry

Teleforms scannable forms

Oracle expertise

Build custom databases

Extend current databases

Bioinformatics Support



Computing/Bioinformatics Core Services

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Getting your GCRC Genetic Study Done

  • Develop Protocol:

    • New protocol: Contact Kelly Taylor, she’ll do most of the work

    • Existing protocol: In many cases existing DNA addendum will work

  • Present to GCRC for approval

    • <100 DNAs, <100 genotypes, no special approval needed

    • >100 DNAs, >100 genotypes, Genetics subcommittee must approve.

  • Perform study

    • DNA collection can be done on GCRC or by FAC

    • DNA extraction by DNA Resources core

    • Genotyping by DNA Resources core

  • Genetic Analyses

    • Can be done by DMAC (additional fee)