Some current issues in QTL identification
This presentation is the property of its rightful owner.
Sponsored Links
1 / 42

Some current issues in QTL identification PowerPoint PPT Presentation


  • 69 Views
  • Uploaded on
  • Presentation posted in: General

Some current issues in QTL identification. Lon Cardon Wellcome Trust Centre for Human Genetics University of Oxford. Acknowledgements:Goncalo Abecasis Stacey Cherny Twin course faculty. LOD. Positional Cloning. Genetics. Chromosome Region. Association Study. Sib pairs. Genomics.

Download Presentation

Some current issues in QTL identification

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


Some current issues in qtl identification

Some current issues in QTL identification

Lon Cardon

Wellcome Trust Centre for Human Genetics

University of Oxford

Acknowledgements:Goncalo Abecasis

Stacey Cherny

Twin course faculty


Some current issues in qtl identification

LOD

Positional Cloning

Genetics

Chromosome Region

Association Study

Sib pairs

Genomics

Candidate Gene Selection/

Polymorphism Detection

Mutation Characterization/

Functional Annotation

Physical Mapping/

Sequencing


Some current issues in qtl identification

Inflammatory Bowel Disease Genome Screen

Hampe et al., Am J Hum Genet, 64:808-816, 1999


Some current issues in qtl identification

Inflammatory Bowel Disease Genome Screen

Hampe et al., Am J Hum Genet, 64:808-816, 1999


Some current issues in qtl identification

Susceptibility locus mapped for Crohn’s Disease


Some current issues in qtl identification

Genome Screens for Linkage in Sib-pairs

1997/98

1999

- Diabetes (IDDM + NIDDM)

- Asthma/atopy

- Osteoporosis

- Obesity

- Multiple Sclerosis

- Rheumatoid arthritis

- Systemic lupus erythematosus

- Ankylosing spondylitis

- Epilepsy

- Inflammatory Bowel Disease

- Celiac Disease

- Psychiatric Disorders (incl. Scz, bipolar)

- Behavioral traits (incl. Personality, panic)

- others missed...

  • - NIDDM

  • Asthma/atopy

  • Psoriasis

  • Inflammatory Bowel Disease

  • - Osteoporosis/Bone Mineral Density

  • - Obesity

  • - Epilepsy

  • - Thyroid disease

  • - Pre-eclampsia

  • - Blood pressure

  • - Psychiatric disorders (incl. Scz, bipolar)

  • Behavioral traits (incl. smoking, alcoholism,

    • autism)

  • - Familial combined hyperlipidemia

  • - Tourette syndrome

  • - Systemic lupus erythematosus

  • - others missed…


Human qtl linkage gene identification successes

0

Well, at least < 5

Human QTL Linkage  Gene Identification Successes


Why so few successes in human qtl mapping

Why so few successes in human QTL mapping?

  • Many valid reasons proposed:

  • Phenotypic complexity (not measured well)

  • Genetic complexity (many genes of small effect, GxE,

  • epistasis)

  • Genotype error

  • Sampling design

  • Statistical methods

  • ….

Most linkage studies have been under-powered (and over-hyped)


Some current issues in qtl identification

QTL Mapping has very low power !

1000 sibs, no parents: markers every 10 cM, each marker H=0.8

QTL

h2=0.33

Kruglyak L, Lander ES. (1995). Am J Hum Genet 57: 439-454


Increasing power to detect linkage in sib pairs

Increasing power to detect linkage in sib-pairs

  • Phenotypic selection

    • Carey & Williamson, 1991, AJHG

    • Eaves & Meyer, 1994, Behav Genet

    • Cardon & Fulker, 1994, AJHG

    • Risch & Zhang, 1996, AJHG


Some current issues in qtl identification

Information Score for Additive Gene Action (p=0.5)

350

300

250

Information score

200

150

100

10

8

6

1

2

3

Sib 2

4

4

5

6

7

2

8

9

10

Decile ranking - Sib 1


Linkage analysis of qtls summary

Linkage Analysis of QTLs-Summary-

  • Spotted history. Few, if any, bona fide successes

  • Power has been large problem

  • Of the few replicated loci, most have used some form of selection

  • EDAC, other selection schemes from large cohorts now underway

  • Genome-scans coming soon

  • Promising beginning for QTL linkage mapping


Some current issues in qtl identification

LOD

Positional Cloning

Genetics

Chromosome Region

Association Study

Sib pairs

Genomics

Candidate Gene Selection/

Polymorphism Detection

Mutation Characterization/

Functional Annotation

Physical Mapping/

Sequencing


Some current issues in qtl identification

Association Analysis

  • Simple genetic basis

    • Short unit of resemblance

    • Population-specific

  • One of easiest genetic study

  • designs

  • Correlate allele frequencies with traits/diseases

  • At core of monogenic & oligo/polygenic trait models

  • Widely used in past 20 years

  • HLA, candidate genes, pharmacogenetics, positional cloning


Some current issues in qtl identification

Angiotensin-1 Converting Enzyme

Keavney et al. (1999) Hum Mol Gen, 7:1745-1751


Evidence for linkage

T-5991C

T-3892C

T-93C

G2215A

G2350A

A-5466C

A-240T

T1237C

I/D

4656(CT)3/2

Evidence for Linkage


Results of ace analysis using vc association model

T-5991C

T-3892C

T-93C

G2215A

G2350A

A-5466C

A-240T

T1237C

I/D

4656(CT)3/2

Results of ACE analysis using VC association model


Some current issues in qtl identification

Alzheimers and ApoE4

Roses, Nature 2000


Some current issues in qtl identification

Association Resolution by Position

Roses, Nature 2000


Some current issues in qtl identification

Decay of Linkage Disequilibrium in a Small Set of Genes


Some current issues in qtl identification

Toward a linkage disequilibrium map of the human genome

LD/haplotype map objective: find regions of high and low ancestral conservation to clarify signal/noise in allelic association studies

History of LD studies in humans:

  • > 10 year ago, emphasis mainly on theory

    • LD measures, decay, population comparisons, …

  • 1989: 1st use of LD for disease mapping: Cystic Fibrosis

  • Recent years, gene-based haplotypes used widely for monogenic mapping

  • Last 2 years: larger scale assessment of common alleles

  • in reference populations


Some current issues in qtl identification

Reich et al, Nature 2001

Eaves et al, Nat Genet 2000

Taillon-Miller et al, Nat Genet 2000

Haplotype Map: Data/Interpretations

Distribution of pairwise LD  ‘average extent of LD’

LD differences in genes

Stephens et al, Science 2001

Johnson et al, Nat Genet 2001

Abecasis et al, AJHG 2001


Some current issues in qtl identification

Haplotype Map: Data/Interpretations

Local patterns of LD … Conserved haplotype segments ... ‘Blocks’

5q31. Daly et al, Nat Genet 2001

MHC class II. Jeffreys et al, Nat Genet 2001

Chr21. Patil et al, Science 2001


Some current issues in qtl identification

Current Status: Data/Interpretations

  • How to define ‘useful’ LD is still unclear

  • Easier to focus on pairwise LD rather than haplotypes.

  • Is this efficient?

  • For common alleles, D’ measure, LD extends ~ 50-60 kb on average

  • For rare alleles, ?

  • There is great variability in regional patterns of LD

  • Explanations, predictors yet unknown

  • Haplotype blocks are detectable and present broadly

  • Size of blocks? How best to define them? Utility of htSNPs?


Some current issues in qtl identification

  • Human Genome Haplotype Map

    • NIH/TSC/Wellcome Trust funded international collaboration (likely)

      • follow-on from human sequencing project & SNP consortium

    • Hierarchical strategy

      • ‘sparse-map’ then more fine

      • Initially use available SNPs

    • Multiple populations

      • some family-based, most likely to be unrelateds

    • Aim is to catalog regions of high LD down to very fine-scale (ie., find big and small blocks)


Human chromosome 22

Human Chromosome 22

  • First human chromosome to be “fully” sequenced

  • Extensive knowledge of genomic landscape

  • Abundance of SNPs and other variants/bp

~34.5 Mb on q-arm; p-arm mostly structural RNA; 679 genes on q

Dunham et al, Nature, 1999


Samples

Samples

  • 7 x 3 generation CEPH families

    • 77 Individuals

    • 59 founder chromosomes

    • 1505 SNPs successfully genotyped

  • 90 Unrelated Caucasian Individuals

    • 1286 SNPs genotyped (1261 overlapping with CEPHs)

  • 51 Unrelated Estonian Individuals

    • 908 SNPs genotyped (594 overlapping with CEPHs)


Some current issues in qtl identification

N = 1505 markers. Median spacing = 15.07kb.

4 gaps > 200 kb. Smallest = 12 bp; largest = 293 kb.


Some current issues in qtl identification

N=1505


Some current issues in qtl identification

Variability in Pairwise LD

D’

r2


Some current issues in qtl identification

Decay of LD on chromosome 22

Means inCEPHs, Unrelateds, Combined &EstonianSamples


Some current issues in qtl identification

Representing LD along a chromosome

  • Following several trends in genetics, genotyping technology outpaced ability to analyze LD information…

  • How to characterize regions of ‘interesting’ linkage disequilibrium?

  • Simply examine average levels across region/chromosome?

  • Fit models to data, look at expectations & specific predictions

  • Consider ‘interesting’ LD tracts as long runs of LD – borrow from extant statistical approaches

  • Look for ‘blocks’ of LD in the genome


Ld along chromosome 22

LD Along Chromosome 22

Average D’

D’ Half-Life

Disequilibrium Fingerprint


Some current issues in qtl identification

Chromosome 22 Haplotype Blocks

Plus 3 individual blocks:

PositionSNPsHaplosLength

4.6-4.8 M116231 kb

8.2-8.4 M8 4264 kb

34.3 M11 3 82 kb


Chr22 high ld 22 27 mb

Chr22 High LD: 22-27 Mb


Chr22 low ld 27 32 mb

Chr22 Low LD: 27-32 Mb


Some current issues in qtl identification

Microsatellite distance

1 Mb/cM

Recombination Pattern on Chromosome 22

60

50

40

cM

30

20

10

0

0

5

10

15

20

25

30

35

Sequence Position (Mb)


Some current issues in qtl identification

Microsatellite distance

1 Mb/cM

Recombination and Gene Density on

Chromosome 22

Gene

Density


Some current issues in qtl identification

Linkage Disequilibrium Map of Chromosome 22

- Summary -

  • LD ‘half-length’ ~ 50 kb, but depends on measure & what is “useful” LD

  • Family & unrelated samples yield consistent patterns

  • Different analytical tools provide complementary views of long blocks

  • 15% chromosome 22 in long LD blocks in these samples (40% in shorter blocks)

  • Why? Selection, selective sweeps? Chromosome structure? Popln age?

  • LD correlated with gene-density, GC content and related repeats.

  • Gene/GC correlations almost entirely collinear with genetic distance.

  • LD patterns can immediately assist positional association studies:

  • Prioritise candidate regions.

  • Use extant genetic maps and simple repeat structures in design & power.


Some current issues in qtl identification

Mapping QTLs in families:

Summary

  • Linkage and association studies follow directly from fundamental biometrical principles.

  • Linkage studies of complex traits can work: All principles of this course apply

  • - power, study design, careful phenotype selection/modelling,

  • comparison of statistical models

  • New information about LD patterns should facilitate association studies

    • - help form a priori hypotheses and guide replication.

16th Annual Course on Methodology for Twins and Families

Advanced workshop: Boulder, Colorado, March 2003


Some current issues in qtl identification

http://ibgwww.colorado.edu/twins2001/schedule.html


  • Login