Behavioral Genetics Topic

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Behavioral GeneticsTopic 9

• Gene Identification

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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

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• 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)

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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

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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

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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)
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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
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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

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Ethnic Group 2
Ethnic Group 1
Combined
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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

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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

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DRD4
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Results
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Association Studies of DRD4and Novelty Seeking
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Meta-Analysis
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Association Studies of DRD4 and Substance Abuse
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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

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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
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DRD2
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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

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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
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I - 100
S
A
II - 100
A
A
A
A
III - 94
O
IV - 89
V - 85
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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

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Linkage Disequilibrium
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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.

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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)

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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

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Are there other explanations for the
DRD2-Alcoholism Association?

• Linkage Disequilibrium
• False positive owing to ethnic mismatching

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DRD2 A1 allele frequencies
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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

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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

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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.
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