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Mendelian & Complex Traits
Quantitative Imaging Genomics
David C. Glahn, PhD
Olin Neuropsychiatry Research Center &
Department of Psychiatry, Yale University
Mendelian Trait
Complex Trait
• A trait influenced by a
single gene producing a
clear pattern of dominant
or recessive inheritance
within families.
• A trait influenced by
multiple genes and their
interactions with each
other and with the
environment.
• Examples: cystic fibrosis,
sickle cell anemia,
hemophilia
• Examples: autism,
schizophrenia,
Alzheimer’s, brain
anatomy, BOLD signal
July 22, 2010
Genetics Terminology 1
Genetics Terminology 2
• Quantitative Trait Locus (QTL), a location,
usually a chromosomal region, implicated as
containing one or more genes that influence
a phenotype of interest
• Quantitative Trait Nucleotide (QTN), a
specific sequence variation that has been
implicated as having a functional effect on a
phenotype of interest
• A QTL may contain multiple QTNs
• Chromosome: a single long string of DNA, humans
have two copies of each chromosome (diploid),
one from mom, one from dad
• Autosome: None sex chromosome (22 in humans)
• Sex chromosome: X or Y chromosome, females
have 2X, males have 1X and 1Y
• Mitochondrial DNA: non-nuclear DNA, inherited
only from the mother
Human Genome
Genetics Terminology 3
23 Chromosomes
~20-25,000 genes
~3 billion base pairs
• Gene: a unit of DNA that codes for a protein
(but the term may be used to include both
coding and non-coding elements)
• Locus: location, sometimes used
interchangably with gene
• Allele: the specific variant you have at a
particular site in the genome, the possible
variants at a locus
Loci, Alleles, Genotypes,
Genetics Terminology 4
• Genotype: the combination of alleles on the
two chromosomes of an individual
• Haplotype: the alleles at different loci being
carried together on the same chromosome
• Phenotype: the trait of interest, some
measurable property of the individual
– Examples: neuroanatomy, neurophysiology,
schizophrenia, bipolar disorder, Alzheimer’s
Within A Gene
A Small Gene: FVII gene (~15 kb)
H115H
1
2
Two loci: letter locus & number locus
Each locus has two alleles: A or B, 1 or 2
The genotype at the letter locus is AB
The haplotype on the first chromosome shown is A1
• Functional & physical unit of
heredity passed from parent
to offspring (pieces of DNA)
• Typically contain information
to make a specific protein
• Composed of nucleotides,
sequence of four organic
bases (Adenine, Guanine,
Cytocine, and Thyamine)
• Matching nucleotides on the
complimentary DNA strands
form a base-pair
How to do Genetics
Question
A294V
9.734 A/G
R353Q
IVS 7
S333S
10.524 G/A
-668 A/C
2
3 4
5
6
7
8
-3216 C/T -628 A/G1a 1b
10.534 T/C
-2987 C/A
3.171 G/A 5.191 A/G 7.161 G/C
260 A/G
3.294 G/A 5.503 T/A 7.453 T/G
9.431 A/G
364 G/A
7.729 G/A
698 T/C 3.380 C/T
9.779 T/C
705 G/A 3.423 G/T
8.695 G/A 9.792 G/A
6.331
G/A
3.928 G/A
710 C/G
9.847 C/T
4.003 G/A 6.448 G/T
723 - 101 bp
6.452 G/T
799 T/C
6.461 + T
806 G/A
811 C/G
833T/C
945 G/A
B
The Gene
• Exon: specifies the mRNA, which is
translated into the series of amino acids in
the protein, coding sequence
• Intron: non-coding, intravening sequence
• Splice site: the juncture between an exon &
an intron
• Promoter, enhancer: regulatory element
(usually non-coding), controls time, place,
amount of transcription
-323 ± 10bp
-401 G/T
-122 T/C
-402 G/A
73 G/A
A
What do you want to know?
11.912 G/A
11.622-3 del AG
11.293-4 ins AA
Sample
Who do you need to study?
Method
How will you use your data?
Questions for the Study of
1) Is this trait influenced by genetic factors? How strong are
these genetic influences?
2) Which traits are influenced by the same genes?
3) Where are the genes that influence a trait?
4) What are the specific genes that influence the trait?
5) What specific genetic variants influence the trait and how
do they interact with each other and with the environment?
Subject Ascertainment Strategies
1. By phenotype: if you’re studying a rare disease, you
must ascertain on phenotype. This is also necessary for
some study designs (TDT, case/control).
2. Randomly: if you’re studying a common disease, you’ll
find it in a random sample. If you’re interested in
multiple traits, ascertaining on one improves power only
for that one. May also want to study normal variation.
3. Ascertainment also depends on (and limits) method of
analysis – TDT, affected relative pair linkage.
Defining Heritability
Six Types of Samples for Genetics
1. Adoptees: separating the effects of genes and family
environment
2. Unrelated individuals: association only, estimation of effect
size after variants are identified
3. Parent-child triads: association in the presence of linkage
(transmission disequilibrium test), heritability/relative risk
4. Twins: heritability, relative risk, genetic correlations, linkage,
association
5. Relative pairs: heritability, relative risk, genetic correlations,
linkage, association
6. Pedigrees: heritability, relative risk, genetic correlations,
linkage, association
Question 1: Heritability
Is this trait influenced
by genetic factors?
How strong are these
genetic influences?
Variance Decomposition
!"#"$%
&#'()"*+#,'-.#/"#0
123-"4*+#,'-.#/"#0
!
2
µ
^ = "x / n
µ
i
Phenotype (P) = Genotype (G) + Environment (E)
^
^
!2 = "(x - µ)2 / n
Almasy & Blangero, Am J Hum Genet, 1998
!
!
!
!
!
!
!
!
2
p
= !g + !e
2
g
= !a + !d
2
e
= ! c + ! eu
2
= total phenotypic
p
2
g
2
e
2
a
2
d
2
2
2
2
2
2
= genetic
= environmental
= additive genetic
= dominance
Broad-Sense Heritability (H2)
• All possible genetic
contributions
!g
2
H= 2
!p
2
– allelic variation (additive
variance)
– dominance variation,
– epistatic (multi-genic)
– interactions,
– maternal and paternal
effects
-a AB
0 2
2
g
a
d
AA
BB
0 d BB
+a
VA = 2pq[a + d(q-p)]2
+a
Narrow-Sense Heritability (h2)
!a
h = 2
!p
2
2
AB
Estimating Additive & Dominate
If the heterozygote is half way between the two
homozygotes, there’s a “dose-response” effect, d is zero,
and there is no dominance.
• Heritability (h2):
the proportion of
the phenotypic
variance in a trait
attributable to the
additive effects of
genes.
! = ! + !
2
-a Defining Dominance
AA
Decomposing Genetic Effects
VD = (2pqd)2
Conceptualizing Heritability
• Heritability estimates vary between 0 and 1
– 0, genetic factors do not influence trait variance
– 1, trait variance is completely under genetic
control
• If h2=0.5, then 50% of phenotypic variation
is due to genetic variation.
– Not that the trait is 50% caused by genetics
• Stronger heritability does not imply simple
genetics
Estimating Heritability with Twins
Falconer’s Method
Estimating Heritability with Twins
• Monozygotic (identical):
• Dizygotic (fraternal): h2=2*(rMZ-rDZ)
VA+VD
1/2 VA + 1/4 VD
• 2 x Difference = VA + 3/2 VD ! h2
rMZ= correlation between monozygotic co-twins
rDZ= correlation between dizygotic co-twins
• Assuming that shared environmental effects
are equal for both types of twins.
Twin Concordances
Limitations of Twins
!"#$%&'$($%)
• Common Environment Unless Raised Apart
• Twins reared apart are difficult to find
• Common prenatal environment;
5)$6/
1%2'7.82-"#'3
9'8.:3-*;'6.-4"5#.-"<'3
5;=;
>3#'%*;'6.-4";"8-"66'.#
>?1;
!5;
1.%'3:*>2.@'3
AB;
Variance Component Approach
Modeling the Phenotype:
p = µ + "# i xi + a + d+ e
µ
Population mean
#
Regression coefficients
x Scaled covariates
a Additive genetic effects
d Dominance genetic effects
e Random environmental effects
– intrauterine competition
• Mother may be physically stressed
• Twin samples are fundamentally less
powerful for QTL localization
Variance Component Approach
2
2
2
$ = 2 %! a + & ! d + "! e
7
# coefficient of relationship between individuals
$ probability that individuals share both alleles IBD
" Kronecker function
Defining Mendelian Relationships
Relatives
Parent-child
Half siblings
Full siblings
Cousins Covariance 1/2VA 1/4VA 1/2VA+ 1/4VA 1/8VA
Heritability
b = 1/2 h2
r = 1/4 h2
r ! 1/2 h2
r = 1/8 h2
Kinship Matrix
2
4
3
5
Dad
1
ignoring interactions and shared
environmental effects
1
Simple Kinship Matrix
Mom
2
3
D
M
1
2
3
D
1
0
%
%
%
M
0
1
%
%
%
1
%
%
1
%
%
2
%
%
%
1
%
3
%
%
%
%
1
Limitations of Heritability Estimates
1
2
3
4
5
1
1
0
0
%
0
2
0
1
0
%
%
3
0
0
1
0
%
4
%
%
0
1
&
5
0
%
%
&
1
1. Heritability is a population level parameter, summarizing
the strength of genetic influences on variation in a trait
among members of the population. It doesn’t tell you
anything about particular individuals.
2. Heritability is an aggregate of the effects of multiple
genes. It tells you nothing about how many genes
influence a phenotype. A high heritability is not
necessarily ‘better’ if it is due to many, many genes.
Relative Risk
Heritable vs. Familial
The risk to a relative of an affected
individual as compared to a
randomly chosen member of the
population, '. 1 - (
• A trait can be familial without being
heritable.
• Genes are not the only thing shared by
members of a family (e.g. diet, exercise,
environmental exposures, etc).
• Nuclear families vs. extended pedigrees
• Adoption studies
Heritability of Volume & Gryi
Bartely et al., Brain, 1997
10 MZ / 9 DZ pairs
Gray-Matter Thickness Heritability
Kremen et al., NeuroImage, 2010
110 MZ / 92 DZ pairs
Vertex-Wide Cortical Thickness
Winkler et al., Unpublished
726 family members
Gray-Matter Thickness Heritability
Thompson et al., Nat Neuro, 2001
10 MZ / 10 DZ pairs
Cortical Thickness & Surface Area
Winkler et al., NeuroImage, 2009
486 family members
Superior Occipitofrontal Fascicle
Hulshoff Pol et al. J. Neurosci, 2006 54 MZ / 58 DZ pairs / 34 Sibs
White-Matter Tracts (DTI) h2
White-Matter Hyperintensity h2
Total Cranial: 0.91
Brain Parenchyma: 0.92
WMH: 0.73
Kochunov et al., NeuroImage, 2010
467 family members
White-Matter Hyperintensity h2
74 MZ / 71 DZ pairs
Task Based fMRI Heritability
• Dorsal anterior
cingulate cortex
• Conflict Processing
• h2=0.38
Whole-brain WMH: 0.72
Subcortical WMH: 0.66
Ependymal WMH: 0.73
Kochunov et al., Stroke, 2009
Carmelli et al., Stroke, 1998
459 family members
Task Based fMRI Heritability
Matthews et al., NeuroImage, 2007
10 MZ / 10 DZ pairs
Resting State fMRI Heritability
h2= 0.424
Koten et al., Science, 2009
10 MZ pairs / 10 sibs
Glahn et al., Proc Nat Sci USA, 2010
333 family members
Heritability Conclusions
Question 2: Pleiotropy
We’ve got heritability!!
Which traits are influenced
by the same genes?
Levels of Pleiotropy
Genetic Correlation (Pleiotropy)
No Pleiotropy
Partial Pleiotropy
Full Pleiotropy
Trait 1
Trait 2
Trait 1
Trait 2
Trait 1
Trait 2
Estimating Pleiotropy
• Genetic correlation ()g): a measure of the
overlap in genetic effects between traits.
• )g varies from -1 to 1
• 0 = no pleiotropy; -1 or 1 = complete
pleiotropy
Cortical Thickness & Surface Area
)p = )g'(h21h22) +)e'((1-h21)(1-h22))
h21 and h22 are the heritabilities of traits 1 and 2
Schmitt et al., Cerebral Cortex, 2008 107 MZ / 47 DZ / 228 others
Winkler et al., NeuroImage, 2009
486 family members
White-Matter Hyperintensity &
Cortical Thinning & IQ
WMH - Executive Function
)g = 0.70
WMH - Mini-Mental State
Exam
)g = 1.0
)g = 1.0/1.0
Carmelli et al., Neurobiol Ageing, 2003
72 MZ / 70 DZ pairs
White Matter Tracts &
Superior longitudinal fasciculus – Spatial DRT: )g = 0.593
Karlsgodt et al., J Neurosci, 2010
Coffee Break
467 family members
Brans et al., J Neurosci, 2010
)g = 1.0/0.7
77 MZ / 84 DZ pairs
Pleiotropy Conclusions