Behavioral Genetics Topic

1
Behavioral GeneticsTopic 9

• Gene Identification

2
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, BRCA-2, APP, MODY-1,-2,-3)
3
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

4
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
• Good for genes of large effect limited power to
  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

5
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
6
Allelic Association

• Advantages
• In principle, very high statistical power
• In principle, can identify causal agent
• Disadvantages
• Need to know functional polymorphisms in a
  candidate gene
• Concern about false-positives due to mis-matching
  cases and controls

7
Challenges of Gene Identification

• 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.

8
Ethnic Group 2
Ethnic Group 1
Combined
9
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

10
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

11
(No Transcript)
12
Results
13
Association Studies of DRD4and Novelty Seeking
14
Association Studies of DRD4 and Substance Abuse
15
Why the Inconsistent Results?

• False positive due to poor matching
• Low power in samples of modest size
• DRD4 effect depends on genetic background
  (epistasis)
• APOE and AD
• DRD4 effect may depend on environmental context
• DRD4 association may be indirect

Keltigangas-Jävinen et al. (2004)
16
Meta-analysis of DRD4 and Personality
Munafo, M.R. et al. (2003). Molecular Psychiatry,
8 471-484.
17
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
18
DRD2
19
If real, how could the association arise?

• Linkage Disequilibrium
• Non-random association of alleles at linked loci
• Can lead to population (indirect) associations
  between non-functional genetic markers and
  phenotypes

20
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
21
I - 100
S
A
II - 100
A
A
A
A
III - 94
O
IV - 89
V - 85
22
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
• In short, it depends on the evolutionary history
  of the population

23
Linkage Disequilibrium
24
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., gt 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)

25
Therefore

• In outbred populations (e.g., the US), LD may not
  extend much beyond 3 - 6 kb ? a genome-wide LD
  study would require 500,000 - 1,000,000 markers!
• Founder or isolated populations may need fewer
• Small of founders, little immigration,
  expansion
• Samii, Costa Rica, Quebec, Iceland, Japan

26
Are there other explanations for the
DRD2-Alcoholism Association?

• Linkage Disequilibrium
• False positive owing to ethnic mismatching

27
DRD2 A1 allele frequencies
28
Genome-Wide Association A Matter of Numbers

• There are 11,000,000 SNPs in the Human Genome
• Strategies
• One polymorphism for every gene 20,000 SNPs
• Polymorphisms that change coding sequence 60,000
  SNPs
• Every 3,000 to 6,000 bases 500,000 to 1,000,000
  SNPs
• Take advantage of the haplotype structure of the
  genome

29
Carlson, C.S. (2004). Mapping complex disease
loci in whole-genome association studies. Nature,
429 446-452.
30
Haplotypes

• Haplotype is a generalization of the concept of
  genotype to multiple loci
• 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

31
Haplotypes

• 3 Genotypes
• AT at locus 1
• CG at locus 2
• GC at locus 3
• Haplotypes (alleles inherited together on same
  chromosome)
• ACG TGC

A
T
C
G
G
C
32
Although 9 markers in block 4, only 4 possible
haplotypes, which can be determined by only 2
markers
Cardon Abecasis (2003). Using haplotype blocks
to map the human genome. Trends in Genetics, 19
135-140.
33
Back to COMT

• Support for a direct (i.e., causal) association
• The polymorphism is functional
• Allelic association studies
• Suggestion that it may be an indirect
  association
• Inconsistent association
• a priori might expect Met allele would be
  high-risk
• Shifman et al. (2002) paper

34
(No Transcript)
35
Genetics and Race
36
Why Are Geneticists Interested in
Ethnicity/Race?

• Disease frequencies vary as a function of
  self-identified race
• Allele frequencies vary as a function of
  self-identified race
• Therefore
• Race needs to be controlled for in genetic
  studies
• Race may provide insights into the origins of
  disease
• Race is also a difficult topic
• Given the history of genetics
• To define

37
Social Construction

• Race was used in an attempt to classify humans
  into discrete, natural groups
• Africans
• Americans
• Asians
• Caucasians
• Oceanians
• Racism involved imbuing these classifications
  with behavioral and hierarchical attributes

38
Biologically Meaningless

• Researchers have unanimously declared there is
  only one race the human race
• New York Times
• there is no basis in the genetic code for race
• Craig Ventner

39
What Does Biologically Meaningless Mean?

• Current genetic data refute the notion that
  races are genetically distinct human populations.
  There are no gene variants that are present in
  all individuals of one population group and in no
  individuals of another.
• Bonham, V.L. et al. (2005). American
  Psychologist, 60 9-15.

40
Out of Africa
41
UNESCO (1950)

• A race, from a biological standpoint, may
  therefore be defined as one of a group of
  populations constituting the species Homo sapiens
  ... by virtue of the isolating barriers which in
  the past kept them more or less separated,
  exhibit certain physical differences ...

42
Bamshad et al. (2004). Deconstructing the
relationship between genetics and race. Nature
Reviews Genetics 5 (8) 598-608.
43
Can we Find a Better Term Than Race?

• Ethnicity
• Emphasizes the cultural, socioeconomic, and
  ideological differences among human groups
• Ancestry
• Defined geographically (Asian, sub-Saharan
  African) or geopolitically (Irish, Vietnamese),
  or culturally (Brahmin, Apache)

44
Genetic variability among groups?

• Variants present in some but not all groups.
  There are few examples
• ALDH2 and alcoholism
• Variants present in all groups but at different
  frequencies. There are many examples
• 825T allele of GNB3 ? obesity hypertension
• (80 AA, 45 Asians, 30 European)
• KCNJ11 ? diabetes
• (20 African, 40 European)
• Majority of drug response genes

45
Goldstein Hirschhorn (2004). In genetic control
of disease, does 'race' matter? Nature Genetics
36 1243-1244.
46
Race-Based Medicine?

• Ashkenazi Jewish Genetic Panel
• The Thrifty Genotype Hypothesis
• General Health Disparities
• Moderate (but not heavy) smoking more strongly
  associated with lung cancer in African-Americans
  than European or Asian-Americans

47