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Transcript
Human Genetics
Behavioral Genetics
Behavior
Some behaviors can be transmitted from
parent to child.
What proportion of a behavior results
from the action of genes?
What proportion of a behavior is learned?
Behavioral genetics is the study of the
genes involved in the development and
regulation of the nervous system.
Genes and Behavior
Early 20th century - Extremes of the
schools
Freud and the psychoanalysis schools
 all environmental
Eugenic movements
 all bad genes
What are the risks of “Blaming Genes”
How do you define a behavior?
need to define the abnormal phenotype
need to clearly demarcate it from the
"normal"phenotype
need to clearly separate it similar "aberrant
behaviors“
 Alcoholism
 Phenotype - characteristic deviant behaviors
associated with excessive consumption of alcohol
 If there is a genetic basis, the phenotype
should be mapped to chromosomal markers
(RFLP, Microsatellites, SNPs)
Critical Periods of Development
Organs develop at different times in
development:
 A critical period can vary.
During its critical period, an organ is
vulnerable to toxin, viruses, and genetic
abnormalities.
Altering the normal development may
cause birth defects.
Tobacco
 About 20% of women still smoke while
they are pregnant
 twice the rate of premature delivery
 infants weigh less than normal – < 5 lbs
 low birth rate is a leading predictor of
infant mortality
Tobacco
 Nicotine constricts the blood vessels of the
placenta

less blood flow to the infant
 Nicotine crosses placenta blood barrier
 affects brain development
 impairs cell growth and mental
development
 IUGR - intrauterine growth retardation
Alcohol
Alcoholism affects about 1-2% women of
child-bearing age
Moderate alcohol during early pregnancy
can cause abnormal development
Fetal Alcohol syndrome 1-2 per 1000
Alcoholics
binge drinking episode
women - 5 or more drinks in one sitting
over 2 or 3 days
Maternal alcohol abuse is the most
common cause of mental retardation
Just one drink a day is believed to cause
fetal alcohol effects-behavior and learning
problems
modest drinking in third trimester
Decrease in birth weight
Constricts placenta blood flow
Hypoxia – decrease growth and
development
Fetal Alcohol Effects
Greatly increase
chance for
spontaneous abortion
IUGR - intrauterine
growth retardation
Mental retardation
Mimics Autism
How do we study behavior?
Model systems
Inbred strains of mice
 role of vasopressin receptors in prairie voles
and mice
 selectively breed for behaviors
Gene for Fidelity- in Rodents
Single genes can have large behavioral
consequences
Male mice - quite promiscuous
Prairie vole - known for its sociable
nature and dedication to one mate
What makes their behavior different?
Why?
Scientists have transformed promiscuous
male mice into more faithful partners and
doting dads by inserting a single gene
(vasopressin 1a receptor) from a prairie
vole.
Hormone vasopressin 1a receptors in the
spatial memory region of the vole's brain
makes them faithful. If not in that region,
the voles are not faithful.
Most behavioral traits are
multifactorial
Attention deficit disorder (ADD) or
Attention deficit/Hyperactivity disorder
(ADHD)
Siblings of affected child show 3-5x greater
risk than those without an affected sibling.
Twins studies indicate ~ 80% heritability.
Linkage studies indicated dopamine pathway
may be involved in ADD/ADHD.
How do we study behavior?
 Model systems
Drosophila
 From the fruit fly – we have learned about
genes that regulate learning, sexual behavior
and motor behavior
 have been cloned using mutational analysis
 many of these genes have human homologs
The brain is composed of
neurons.
Transmitting neuron
(Presynaptic neuron)
Receiving neuron
(Postsynaptic neuron)
Axon
Synapse
Direction of action potential
Transmission of information between
neurons involves neurotransmitters.
Cloninger’s Basic Personality
Dimensions
Novelty seeking
Avoidance of harm
Reward dependence
Persistence.
Self-directedness (accept yourself)
Cooperativeness (accept others)
Self-transcendence (feel part of nature)
Test: Temperament and Character
Inventory
Australian Twin Study
Earlier Twin Studies showed additive genetic
effects accounted for 48% of the variance in Selftranscendence scores for men and women alike.
http://genepi.qimr.edu.au/staff/nick_pdf/CV361.pdf
The tridimensional personality
questionnaire (TPQ)
Designed to measure aspects of
temperament:




Novelty Seeking
Harm Avoidance
Reward Dependence
Persistence
TPQ example Novelty Seeking
questions
True / False
I often try new things just for fun or thrills,
even if most people think it is a waste of
time. (T)
I often do things based on how I feel at
the moment without thinking about how
they were done in the past. (T)
I am much more controlled than most
people. (F)
Novelty-Seeking Gene
Recreational drugs like cocaine, nicotine and
alcohol may work through the brain's dopamine
system.
In Parkinson's disease, the dopamineproducing cells of the brain gradually
degenerate. Parkinson’s patients are unusually
low in novelty-seeking behavior.
The dopamine system has been suggested by
Cloninger to play a role in impulsive,
extravagant behavior.
Novelty-Seeking Gene
High score on the Novelty Seeking scale:
 impulsive, exploratory, fickle, excitable,
quick-tempered, extravagant
Low score on the Novelty Seeking scale:
 reflective, rigid, loyal, stoic, slow-tempered,
frugal
Novelty-Seeking Gene
Dopamine D4 receptor (D4DR) exon III
polymorphism associated with the human
personality trait of Novelty Seeking.
Richard Ebstein et al., 1996
Population and familial association
between the D4 dopamine receptor gene
and measures of Novelty Seeking.
Jonathan Benjamin, et al., 1996
Dean Hamer lab, NIH
Novelty-Seeking Gene
Studies have shown that the number of
exon III repeats can affect the affinity of
ligand (proteins or drugs) that bind to the
receptor.
D4DR is expressed in limbic areas
involved in cognition and emotion.
Novelty-Seeking Gene
Research on animals, as well as extensive
studies of human twins of both the identical and
fraternal variety, indicate that about half of
novelty-seeking behavior is attributable to
genes, the other half to as-yet ill-defined
environmental circumstances.
The D4 dopamine receptor may account for
perhaps 10 % of the difference in noveltyseeking behavior between persons.
Novelty-Seeking Gene
Some studies have failed to replicate the
initial findings.
The Dopamine D4 Receptor Gene and
Novelty Seeking
Anil K. Malhorta, M.D., and David
Goldman, M.D.
Finnish Population
Novelty-Seeking Gene
Were the early results just due to chance
results in small or unusual populations, and not
a real effect of D4DR, or not representative of
the general population?
Further evidence for a modulation of Novelty
Seeking by DRD4 exon III, 5-HTTLPR and
COMT val/met variants.
A. Strobel et al. 2003
 (Same group as prior report)
Novelty-Seeking Gene
Benjamin et al. had found:
 Novelty Seeking scores are higher in the
presence of the DRD4 exon III 7-repeat allele
in the absence of the short (s) allele of the
serotonin transporter gene promoter-linked
polymorphic region (5-HTTLPR) and in the
presence of the val/met genotype of the
COMT gene.
Novelty-Seeking Gene
Benjamin suggested "that failure to
replicate associations between
personality factors and some genes may
be partially due to the presence of
additional modifying common
polymorphisms".
Novelty-Seeking Gene
Strobel et al. decided to see if this effect
explained their failure to find an
association in their German population.
Genotyped 5-HTTLPR and COMT
val/met in their prior subjects.
Hypothesis
In the group defined by 5-HTTLPR 1/1
genotype and COMT val/val genotype,
individuals with the DRD4 exon III 7repeat allele would have higher Novelty
Seeking scores than those without the
repeat.
Results
 Found a significant difference between those with and
without the 7-repeat allele, p = 0.035 after accounting
for differences in the other polymorphisms.
 The study shows that the failure to detect an effect (due
to D4DR polymorphisms) could be explained by the
presence of additional modifying common
polymorphisms.
 Inclusion of additional genetic variations may help
resolve some of the inconsistencies in human genepersonality/behavior correlation studies.
http://www.nature.com/mp/journal/v8/n10/pdf/4
001367a.pdf
Review Article of many studies
Criminal Behavior/Violence
Classic nature versus nurture arguments
1993 study of a Dutch family describes
one long family history of " a syndrome of
borderline mental retardation and
abnormal behavior"
Co-segregation of mental retardation, aggressive behavior
and a mutation in monoamine oxidase type A gene (MAOA).
* - males known to have the mutated MAOA allele.
Δ - males known to have the normal MAOA allele
Monoamine oxidase type A gene
Familial defect?
 Single nucleotide substitution in the enzyme
monoamine oxidase A (MAOA)
 renders the enzyme non-functional
MAOA is a key enzyme
 required to breakdown several neurotransmitters
 dopamine, serotonin and noradrenaline.
 behavioral defects not unexpected
What if one inherits a slight mental impairment
that interferes with a persons ability to cope
with frustrating situations -resulting in violence?
Genetic and Environmental Effects
Role of Genotype in the Cycle of Violence in
Maltreated Children
Avshalom Caspi et al. 2002
• wanted to identify gene variants that, given
specific environmental triggers, predispose
individuals to anti-social behavior
• Low MAOA activity in abused boys led to
criminal behavior
• Low MAOA by itself was normal
• High MAOA in abused boys had less criminal
behavior observed, but more than unabused.
Genetic control of human behavior
 Supported by pedigree analysis
 Family studies
 Twin and adoption studies
 Identification of susceptibility genes
 Identification of single gene mutations
 Most behaviors are complex
 Many genes contribute to the expression of the trait
 Behavioral traits are not easily measured
 Subjective rather than objective measurements
If Personality Runs in Families, so
too does Mental Illness
Prior to 1966, schizophrenia was thought
to be related to environmental conditions
and poor parenting
1966 - key study showed Infants put up
for adoption by schizophrenic mothers
showed the same rate of schizophrenia
expected for being raised by a
schizophrenic mother
Disease
Prevalence %
Alzheimer disease
Anxiety
Phobias
Post-traumatic stress disorder
Generalized anxiety disorder
Obsessive compulsive disorder
Panic disorder
Attention deficit hyperactivity disorder
Autism
Drug addiction
Eating disorders
Mood disorders
Major depression
Bipolar disorder
Schizophrenia
4.0
8.0
2.5
1.8
1.5
1.2
1.0
2.0
0.1
4.0
3.0
7.0
6.0
1.0
1.3
Single Gene Mutations and
Abnormal Behavior
 PKU: phenylketonuria
 Leads to severe metal retardation
 Single gene defect - major behavioral mutation
 Avoid Phenylalanine in diet- screening for infants to detect
 Lesch-Nyhan Syndrome








X-linked recessive trait
affects 1 in 100,000 males
inborn error of metabolism
lack the enzyme hypoxanthine-guanine
phosphoribosyltransferase
High level of uric acid in the blood and urine
Strong tendency for self-mutilation
Symptoms fully develop by ages 2-4
Most die before age 20
Huntington's Disease
Autosomal dominant disease
 Late onset - mid-adult
First observed characteristic
 Involuntary muscle movements of arms, legs, torso
Later - personality changes, agitated behavior
and dementia
Associated with expanding CAG triplet repeats
Disease runs a 10-15 yr course of progressively
worsening condition
Autopsy show severe loss of brain areas
Gene product - Huntingtin
House keeping neuron protein
Normal brain
Huntington’s diseased brain
Relationships of genetic defects
and abnormal behavior
PKU and Lesch-Nyhan
 build up toxic chemicals that neurons are very
sensitive to.
Huntington's
 slow progressive death of neurons
 MAOA




aggressive behavior gene
a single gene mutation
an inborn error of metabolism
persons are basically functional - but have improper
control of behavior when stressed by fear, anger,
frustration
Eating disorders are a behavioral
trait
Anorexia nervosa
 psychological perception of obesity and
intentional starvation
Bulimia
 psychological perception of obesity and
intentional vomiting
Muscle dysmorphia
 results from steroid consumption to develop
enlarged musculature
Anorexia nervosa
Women in U.S. have 5% lifetime risk
Risk of mortality due to anorexia is 15-21%.
Individuals with anorexia nervosa have 2.5%
risk of second eating disorder.
10% of cases are males.
Heritability of 0.5 - 0.8
e.g. 9/16 MZ twins concordant versus 1/14 DZ
twins
No causal genes have been identified to date.
Sleep Disorders
Without sleep animals die. The function
of sleep remains unclear.
Genetic contributions are indicated by
heritability among families and
identification of genes in model systems.
Environment influence is great. Sleepwake cycles are regulated in part by light
via the suprachiasmatic nucleus in the
brain.
Narcolepsy with cataplexy
Daytime sleepiness with tendency to rapidly fall
asleep (narcolepsy) and periods of muscle
weakness (cataplexy)
Genetic contribution is indicated:
 0.02-0.06% general population in US and Europe
 1-2% risk with first degree relative
 25-31% concordance among MZ twins
Model of narcolepsy in dogs:
 Fully penetrant autosomal recessive trait due to
allele at gene canarc-1.
 http://www.youtube.com/watch?v=NSKO39HIkAo
Familial advanced sleep phase syndrome
 Drug addiction produces stable, not transient, changes in
the brain
 Heritability is 0.4-0.6
 Twin and adoption studies support role of genes in drug
addiction.
 Tolerance
 the need to take more of a drug to achieve the same effect
 Dependence
 the onset of withdrawal symptoms with cessation of drug
Mood Disorders
Moods are defined as sustained emotions
Affect – short term expression of emotion
Affective disorders (mood disorders)
 Behavioral disorders associated with manic and/or
depressive syndromes
Two basic classes of affective disorders
 unipolar – periods of prolonged depression
 bipolar - cycles of depression that alternate with
periods of elation
Mood Disorders
Life time risk of a clinically identifiable affective
disorder is 8-9%
1 out of 10
Depression is the most common (unipolar
disorder)




More common in females than males (2:1)
Often begins in your 40-50s
Often recurrent and protracted
weight loss, insomnia, poor concentration, irritability,
anxiety and lack of interest of surrounding events
What is the evidence that mood
disorders have a genetic component?
Twin studies
 57% concordance for MZ
 14% concordance in for DZ
Attempts to map the genes have been
generally unsuccessful
 Failure to find linkage
 Novel techniques are being used to map
these genes
Bipolar Disorders
 About 1% of the US population suffers from bipolar
disorders
 Age of onset can be as early as adolescence, often occurs in
20s and 30s
 Males and females similar
 hyperactivity, acceleration of thought process, low
attention span, creativity and feelings of elation and
power
 Many manic depressives are highly creative people
 “thin line that separates genius and madness”
 manic depressive have unique patterns of metabolism
and blood flow in the prefrontal cortex-a part of the
brain associated with intellect
Bipolar Disorder Spectrum
Symptoms include dramatic moods swings
between euphoria and severe depression;
patients may have hallucinations or delusions.
 Bipolar disorder I More severe symptoms
 Bipolar disorder II. Less severe symptoms
Study researchers say health professionals
should recognize a third and milder category -sub-threshold bipolar disorder.
In 2006, NIMH researcher Kathleen Merikangas
estimated 2.6% of the U.S. population (5.7
million American adults) suffered from bipolar
disorder in any given year.
Lifetime and 12-Month Prevalence of Bipolar Spectrum Disorder in the National Comorbidity
Survey Replication. Merikangas, KR et al. Arch Gen Psychiatry. 2007;64(5):543-552.
Bipolar Disorder Spectrum
BPD is a leading cause of premature mortality
due to suicide and associated medical
conditions, such as diabetes mellitus and
cardiovascular disease.
Researchers discovered many patients were in
treatment but not getting the correct
medications.
80% of cases begin between the ages of 18
and 24 years.
Increasing number of childhood bipolar
diagnoses
 http://www.nytimes.com/2008/09/14/magazine/14bip
olar-t.html?pagewanted=1&em
Bipolar Disorder Spectrum
When patients who met the diagnostic criteria for
sub-threshold bipolar disorder were included,
Merikangas and NIMH colleagues concluded
4.4% of U.S. adults have some degree of bipolar
illness during some point in their lives.
The lifetime incidence of bipolar I and bipolar II
was roughly 1% each in the surveyed population
and 2.4% for sub-threshold bipolar disorder.
"The [findings] reinforce the argument of other
researchers that clinically significant subthreshold bipolar disorder is at least as common
as threshold bipolar disorder," Merikangas and
colleagues wrote in the May issue of Archives of
General Psychiatry.
Inheritance of Bipolar Disorder
Diagnostic criteria for bipolar affective disorder
define a phenotype that is highly heritable, yet
clinically variable.
A better definition could improve genetic and
other studies, but the best approach is unclear.
Variable occurrence of psychosis, suicidality,
and rapid cycling among people with the bipolar
I subtype.
The clinical variability may reflect underlying
heterogeneity at the biological and genetic
levels.
What Is Familial About Familial Bipolar Disorder? Schulze, TG et al. Arch
Gen Psychiatry. 2006;63:1368-1376.
Inheritance of Bipolar Disorder
Gene-mapping benefits from an approach that
seeks to decrease clinical variability among
cases while maintaining the high heritability that
makes BP a good target for gene mapping
efforts. This is referred to as "refining the
phenotype.“
Is BP caused by many genes of small
heritability, or is it actually more than one
syndrome, caused by different genes which
cause similar symptoms?
What Is Familial About Familial Bipolar Disorder? Schulze, TG et al. Arch
Gen Psychiatry. 2006;63:1368-1376.
Inheritance of Bipolar Disorder
Family studies indicated definitions of the
affected phenotype of BPAD might usefully
consider co-morbid conditions and social
functioning along with traditional symptoms.
“People whose bipolar disorder is complicated
by substance abuse, psychosis, and poor social
relations may well differ genetically from those
whose illness shows none of these features.”
What Is Familial About Familial Bipolar Disorder? Schulze, TG et al. Arch
Gen Psychiatry. 2006;63:1368-1376.
Columbia Bipolar Genetic Study
In 1986, the Columbia Bipolar Genetic
Study began studying generations of
families with bipolar illness.
Goal is to search for bipolar disease
genes will lead to improved diagnosis,
treatment, early intervention, and
prevention of bipolar illness.
http://bipolar.hs.columbia.edu/identify.htm
How are genes identified?
Locate research participants
 Locate and interview a large number of
families that have a significant number of
members with the illness.
 Confirm key family members' history through
phone interviews and available medical
records.
Collect blood samples
 Extract DNA - the genetic material - from the
blood cells
http://bipolar.hs.columbia.edu/identify.htm
How are genes identified?
Scan the DNA
 Genetic markers are variations in the DNA that are
used for identification purposes. For the most part,
they occur naturally and have no causative role.
Scientists use genetic markers to locate genes, just
as travelers use landmarks to locate destinations.
Genetic markers are often referred to as "signposts"
along the DNA.
 The DNA is scanned in the laboratory for linkage
between the markers and the occurrence of the
disorder.
http://bipolar.hs.columbia.edu/identify.htm
How are genes identified?
Establish Linkage
 Linkage refers to a a statistical association
between a genetic marker and the
occurrence of bipolar disorder within a family
or families.
 If linkage is established, specialized
molecular genetic techniques are used to
isolate the gene itself. Multiple steps are
involved to narrow the search for the gene or
genes involved.
http://bipolar.hs.columbia.edu/identify.htm
How are genes identified?
Analyze the gene
 Determine its DNA sequence.
 Compare the gene from an individual with bipolar
disorder with the same gene from an unaffected
individual. Look for sequence differences in the gene
that could be helpful in diagnosis.
 Identify the gene's "product" to learn how it affects
the brain. For example, the gene might produce an
enzyme or neurotransmitter that affects brain
function.
 Once the gene's "product" is identified, and its
relationship to bipolar disorder is understood,
treatment can be developed
http://bipolar.hs.columbia.edu/identify.htm
Mechanism
of Drug
Action
for SRI
Mood disorders
Serotonin, a neurotransmitter, can affect mood,
emotion, appetite and sleep
Many antidepressive drugs are serotonin
reuptake inhibitors (SSRIs) including Prozac, Paxil
and Zoloft.
Schizophrenia
A disorder marked by the loss of the ability to
organize thoughts and perceptions leading to
withdrawal from reality.
Affects 1% of worldwide population.
Progression of disorder:
 Difficulty paying attention
 Memory and learning skills affected
 Psychosis (17-27 males, 20-37 females) delusions
and hallucinations
up to 50% of all hospitalized, mentally ill and
mentally retarded individuals are schizophrenic
Two models of Schizophrenia
Genetics primary and environment
secondary
Environment primary and genetic
secondary
There appears to be a genetic basis, but
environmental inputs necessary for full
expression
Risk Factors for Schizophrenia
You have a 15% lifetime risk of
developing schizophrenia if a relative has
schizophrenia compared to 1% among
unrelated individuals.
Environmental Risk Factors







Maternal malnutrition
Infection by Borna virus
Fetal oxygen deprivation
Obstetric or birth complication
Psychoactive drug use (PCP)
Traumatic brain injury
Herpes infection at time of birth
Lifetime risk for schizophrenia
Tourette syndrome
 Motor and behavioral disorder
Hard to follow it inheritance
About 10% of patients have a family
history
33:1 males
Onset is between 2 and 14 years of age
Alzheimer Disease
Loss of memory with progressive dementia
Development of brain lesions
 Occurs in about 10% of the population over age 50
 Occurs in about 50% of those over age 80
senile plaques
 composed of amyloid beta-protein
Alzheimer patients - accumulate plaques faster
and in greater numbers
both genetic components and environmental
components have been identified
Types of inherited Alzheimer
Disease (AD)
 AD1 -early onset Alzheimer (AD1)
 mutations in amyloid beta-protein gene(C21)
 autosomal dominant
 AD2 - associated with allele APOE*4 (C19)
 AD3 - mutation in a membrane protein (C14)
 Hannah – 1880
 1974 Hannah’s grandson and great-grandson, constructed a
family pedigree
 1992 gene was cloned
 presenilin 1
 receptor located in the golgi membrane
 AD4 - mutation in a membrane bound protein (C1)
Environmental factors
aluminum
 often found in the amyloid deposits
Prion-like molecules
 Prions are proteins that cause several types
of disorders
 often neurodegenerative
 best known - mad cow disease
Is homosexuality inherited?
Is homosexuality inherited?
1980, American Psychiatric Association
removed homosexuality as a disease.
Reclassified as a simple variant form of human
behavior
Pooling data from several studies using twins
 57% of MZ twin brothers of gay men are
themselves gay
 24% of DZ twin brothers of gay men are themselves
gay
 50% of MZ twin sisters of gay women are
themselves gay
 16% of DZ twin sisters of gay women are
themselves gay
Is homosexuality inherited?
Repeatedly show that homosexuality clusters in
families
Pedigrees indicated a much higher rate of gay
brothers, uncles and male cousins in these
families than expected for the general
population
Most apparent gay inheritance follows maternal
lines rather than paternal lines
Suggests that genes regulating sexual
orientation are present on the X chromosome
Is homosexuality inherited?
X-linked inheritance is supported by
inheritance of DNA markers
33 out of 40 pairs of gay brothers all have
exactly the same 5 alleles of five nearby
markers on the X chromosome
heterosexual brothers of the same
families do not have the same full set of
all five alleles
Intelligence
http://www.sciam.com/article.cfm?id=sear
ching-for-intelligence-in-our-genes
Summary: Genes and behavior
 Some abnormal behaviors have been traced to single
gene mutations
 Most are complex multifactorial traits
 There is great difficulty in defining a behavioral phenotype
 Complex environmental components
 Basic issues in defining an abnormal behavior
phenotype
 It is subjective
 We have to discriminate between the normal variants
and what is truly abnormal
 Quiet, shy people vs boisterous, aggressive individuals
 Culture is a major player - society defines the norms