The Genetics of Complex Traits:

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The Genetics of Complex Traits What Are the
Implications for Education? Michael J.
Dougherty Director of Education,
ASHG mdougherty_at_ashg.org NCHPEG Meeting,
September 23, 2009
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TIMSS, 2008
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General trend in U.S. science achievement from
fourth to twelfth grade is downward.
. . . there is actually a steady decline, not a
sudden drop, in performance as students progress
through school . . . American Institutes for
Research, 2007
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How does genetics education fare in America?
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Prevalence of misconceptions by genetics topic
500 essays chosen at random (20 of total
submitted) systematically reviewed for
misconceptions. From Shaw, et al, Genetics 178
1157, 2008.
55.6 had one misconception 20.2 had two
or more
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What does recent research indicate about
single-gene disorders and what do we teach?

• Phenylketonuria (PKU)
• Mutations in phenylalanine hydroxylase gene (PAH)
  can cause phenylketonuria. Autosomal recessive.
• Phenotypically there are at least four clinical
  phenotypes classic PKU, moderate, mild, mild
  hyperphenylalaninemia
• Israeli study, n180, Bercovich et al, J. Hum.
  Genet., 2008
• - Only 63 of metabolic phenotypes could be
  predicted from exonic mutations.
• Phenotypic inconsistencies existed when PAH had
  more than one mutation.

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Ataxia telangiectasia Autosomal recessive ATM
rare neurodegenerative disorder
(Smirnov and Cheung, Am J Hum Genet,
2008) Recessive expression Dominant
expression
Carriers resemble AT patients.
Carriers resemble noncarriers.
i.e., ATM genotype is associated with the
differential expression of other genes.
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• Why is this complexity important?
• May help explain why
• - ATM mutations are susceptibility alleles for
  breast cancer.
• Carriers have increased risk of heart disease
  (pleiotropy or polygeny?).
• - Heterozygous ATM mice have increased risk of
  cancer and metabolic syndrome.

How common is this variation in monogenic trait
phenotype likely to be? CF- carriers have
increased risk of asthma 1500 mutations
variable symptom severity. Gaucher- tremendous
symptom variation in patients carriers have
increased risk of parkinsonism. FFI and CJD-
(autosomal dominant) second-site mutations in
PRNP were thought to be determinative of
phenotype however, variation in pathology and
clinical manifestation implicate other factors.
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Do we teach single-gene traits and disorders in
all their complexity?
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What is the most common tool used to teach
genetics?
Should this be the first and most common
heuristic we use with our students?
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If everyone on both sides of your family is
tall, you are going to be tall. If half are tall
and half are short, you have a 50/50 chance of
being either tall or short. You also have the
possibility of ending up somewhere in the middle.
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If monogenic disease shows such complexity, how
should we think about hypertension, diabetes,
weight?
Consider the difference in phenotype distribution
between single-gene and complex traits.
What causes such a distribution?
Are such traits common?
Genes Environment
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Establishing population references for blood
glucose and lipids
(Bismenya, et al Afr Health Sci. 2006 December
6(4) 247253)
Study 183 university students Blood samples
analyzed
Results Near-Gaussian distributions for glucose,
total cholesterol, HDL, and LDL
What do these results suggest about the
underlying genetics and how can we study such
traits?
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Genome-wide association study (or GWAS) Compare
phenotypic cases to controls by comparing
genetic differences at many different loci called
SNPs. - Essentially a hypothesis generation
technique made possible by high-throughput
sequencing technology and massive computing power.
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What are SNPs?
Single-nucleotide polymorphisms
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GWA study of height (Weedon et al, Nature
Genetics, 2008)
Red dots represent SNPs with P lt 5 x 10-7 in
stage 1 and 2 analysis.
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What important educational messages are emerging
from GWA studies?
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• In Weedon study
• - GWAS and genotyping on 30,000 individuals led
  to 20 variants associated with height.
• Together, the 20 SNPs explain 3 of height
  variation.
• As of mid-2008, there were a total of 54
  validated SNP variants for height (Visscher).
  Implicated genes signaling, ECM, cancer.

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What effect would learning through these examples
have on students understanding of patterns of
inheritance and the nature of genes?
How might genetics principles related to complex
traits contribute to a more informed public and
better health care?
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Genetic variation and common disease (Adeyemo and
Rotimi, Public Health Genomics, 2009) Used GWAS
to investigate loci showing strong and consistent
association with several common diseases. -
Studied 11 populations estimated allele freq.
using HapMap data Conclusions a) wide
variation in allele frequencies across
populations, up to 40-fold b) FST, a measure
of population differentiation due to drift,
varied widely for the susceptibility
loci 0.12- HapMap autosomal avg. (0 would mean
no genetic substructure, random mating,
etc) 0.019 - .201 for type 2 diabetes 0.022 -
.520 for prostate cancer Health risk estimated
from any of these risk alleles is likely to show
wide variation across populations simply as a
function of its frequency, and this risk
difference may be amplified by gene-gene and
gene-environment interactions.
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How are the results of GWAS likely to be most
useful?
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If we focus on genetics alone, can we explain
continuous distributions?
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Will students understand this message?
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Some genotypes may predispose to certain
conditions only in the presence of environmental
triggers. Genetic polymorphism affecting severe
depression. Data from A. Caspi, et al. 2003.
Science 274 1527. Note A recent meta-analysis
by Risch, et al. (JAMA, 2009, 301(23) 2462-71)
supports a link between stress and depression but
found no link between serotonin transporter
genotype, alone or in combination with stress.
The environment is, of course, crucial to complex
trait expression, as it is for single-gene
disorders.
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Environmental influence on phenotype Do we teach
it?
Classic experiments After 100 generations of
inbreeding, mice continue to show metabolic
variability (Storrs and Williams, PNAS,
1968). The variability in growth of plant clones
at different elevations (Clausen, Keck, and
Hiesey, 1940s and 1950s) High school
curriculum Five out of six leading high school
texts lack a sound discussion of incomplete
penetrance (and most fail to distinguish it from
variable expressivity), let alone genetic and
environmental modifiers contributing to it (e.g.,
the influence of pregnancy and smoking on
carriers of BRCA1/2). - Also, missing from a
majority gene-environment interactions and the
potential influence of these interactions on
disease (from L. Doyle, 2009)
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An alternative genetics education
paradigm Inverting the curriculum
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A Continuum of Genetic Influence
Trauma Height, weight, CVD CF, HD, AT Language
spoken ------Cancer------ Schizophrenia