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Behavioral Genetics Topic

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'Human genetics is now at a critical juncture. ... Genetics in Medicine 4:45-61. ... Using haplotype blocks to map the human genome. Trends in Genetics, 19: 135-140. ... – PowerPoint PPT presentation

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Title: Behavioral Genetics Topic


1
Behavioral GeneticsTopic 9
  • Gene Identification

2
Why Search for Behavioral Genes?
  • Gene identification would confirm genetic effects
  • Identify the physiological basis of behavior
    identify interventions
  • Classification of behavior and behavioral
    disorders
  • Genotype-environment interaction

3
  • Human genetics is now at a critical juncture.
    The molecular methods used to identify the gens
    underlying rare mendelian syndromes are failing
    to find the numerous genes causing more common
    non-mendelian diseases.
  • Neil J. Risch (2000, Nature, 405200)

4
Search Strategies (Where?)
  • Non-targeted
  • genome-wide
  • Targeted
  • Chromosomal anomaly (e.g., partial trisomy 5 and
    SZ, VCFS)
  • Biological-based hypotheses (e.g., DRD4 and
    Novelty-seeking)
  • Animal models
  • Positive linkage result from a non-targeted
    search
  • Micro-array findings

5
Search Methods (How?)
  • Linkage analysis (w/i family association)
  • Advantages
  • Feasible to implement genome-wide (systematic
    comprehensive) dont need to have hypotheses
    about location or mechanism
  • relative to alternatives, low false positive rate
  • Disadvantages
  • Limited power detect genes accounting for 5 or
    more of the phenotypic variance
  • Limited resolution tight linkage can be millions
    of bases away
  • Never finds the gene, rather at best identifies a
    region

6
Mendel vs. Galton, Redux?
  • Galtonian
  • Multiple genes
  • Common (?)
  • Weak phenotype-genotype correlation
  • Mendelian
  • Single gene
  • Rare
  • Strong phenotype-genotype correlation

Positional cloning strategy has been very
successful in mapping genes that are rare and
have large phenotypic effect, even if for common
disease (BRCA-1, BRAC-2, APP, MODY-1,-2,-3)
7
Search Methods cont.
  • Allelic Association association between allele
    status and phenotype in unrelated individuals.
    Population-level association

Stomach Cancer

-
O
40
60
Not O (A,B,AB)
40
60
8
Allelic Association
  • Advantages
  • In principle, very high statistical power
  • In principle, can identify causal agent
  • Disadvantages
  • Need functional polymorphisms in a candidate gene
  • Concern about false-positives due to mis-matching
    cases and controls

9
Ethnic Group 2
Ethnic Group 1
Combined
10
The Confounding Role of Ethnicity
  • In candidate gene studies, if
  • The phenotype (disorder) varies as a function of
    ethnicity
  • The genetic polymorphism varies in frequency as a
    function of ethnicity
  • Then,
  • An artifactual association between genetic
    polymorphism and disorder can be observed

11
Ebstein et al. (1996)
  • Phenotype Personality trait of novelty-seeking
  • Sample 124 young Israelis
  • Genotype Variable 48 base repeat sequence in
    Dopamine D4 Receptor gene (DRD4)
  • Finding 7 repeat allele associated with higher
    novelty seeking

12
DRD4
13
Results
14
Association Studies of DRD4and Novelty Seeking
15
Meta-Analysis
16
Association Studies of DRD4 and Substance Abuse
17
Why the Inconsistent Results?
  • False positive due to poor matching
  • Low power in samples of modest size
  • DRD4 effect depends on genetic background
    (epistasis)
  • Experimental studies in mouse
  • APOE and AD
  • False positive due to low a priori likelihood

18
Blum et al. (1990)
  • Phenotype Alcoholism
  • Genotype A1/A2 allele at DRD2
  • Sample 35 alcoholics and 35 non-alcoholics
  • Finding

Not Alc
Alc
7 (20)
24 (69)
A1
A2
11
28
19
DRD2
20
If real, how could the association arise?
  • Linkage Disequilibrium
  • Non-random association of alleles at linked loci
  • Can lead to population associations between
    non-functional genetic markers and phenotypes

21
Non-Sz, O-blood type Mother
Sz, A-blood type Dad
s
s
s
S
O
O
O
A
Suppose 1. This is the original mutation
2. Distance is q .05 3.
Everyone has 4 children
22
I - 100
S
A
II - 100
A
A
A
A
III - 94
O
IV - 89
V - 85
23
Linkage Disequilibrium Mapping
  • Linkage disequilibrium will be a function of
  • How tightly linked the two loci are
  • The number of generations since introduction of
    the original mutational event
  • Whether the mutation has been introduced more
    than once
  • In short, it depends on the evolutionary history
    of the population

24
Linkage Disequilibrium
25
Challenges of Gene Identification
detection of linkage and positional cloning of
specific disease-susceptibility loci remains
elusive. -- Altmüller et al. (2001). AJHG, 69
936-950
  • of the 166 putative associations which have been
    studied three or more times, only 6 have been
    consistently replicated.
  • Hirschhorn et al. (2002). A comprehensive review
    of genetic association studies. Genetics in
    Medicine 445-61.

26
Common Disease-Common Variant (CDCV) Hypothesis
  • The heritable basis of common, complex disease
    owe primarily to alleles that are
  • Relatively common (i.e., not rare, e.g., 10)
  • Experience little selective pressure (i.e., only
    disadvantageous when combined with other
    mutations)
  • Ancient (i.e., introduced more than 5000 Gs or
    100,000 yrs ago)

27
Therefore
  • In outbred populations (e.g., the US), LD may not
    extend much beyond 3 kb ? a genome-wide LD study
    would require 500,000 markers !
  • Founder or isolated populations may need fewer
  • Small of founders, little immigration,
    expansion
  • Samii, Costa Rica, Quebec, Iceland, Japan

28
Are there other explanations for the
DRD2-Alcoholism Association?
  • Linkage Disequilibrium
  • False positive owing to ethnic mismatching

29
DRD2 A1 allele frequencies
30
Is it really going to take genome-wide studies
with 500,000 markers to map complex diseases?
  • Validity of CDCV hypothesis
  • Genome-wide association study of functional
    SNPs ( 60,000-100,000)
  • HapMap project

31
Haplotypes
  • Allelic constitution of multiple loci on a single
    chromosome
  • Recombination is not random, but rather there are
    recombination hot spots
  • This gives rise to blocks of DNA (haplotypes)
    where there is very little recombination w/i
    blocks but strong recombination between blocks

32
Although 9 markers in block 4, only 4 possible
haplotypes, which can be determined by only 3
markers
Cardon Abecasis (2003). Using haplotype blocks
to map the human genome. Trends in Genetics, 19
135-140.
33
 
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