Transcript DNA and Gene Expression

Health Psychology and Aging
Health Psychology
• Also, “behavioural medicine”
• Role of behaviour in promoting health,
preventing and treating disease
• New
• Relatively little behavioural genetics work
Body Weight
• Genetic factors account for majority of variance in
weight
–
–
–
–
–
–
MZ, reared together = 0.8
MZ, reared apart = 0.72
DZ, reared together = 0.43
Biological parents & offspring = 0.26
Biological parents & adopted away offspring = 0.23
Adoptive parents & adopted offspring = 0.01
• Heritability about 70%
• Shared environment effects low
Obesity
• Natural energy reserves (fatty tissue)
exceeds healthy limits
• Absolute or relative terms
• Body mass index
– Weight/height2
– Exceeds 30kg/m2
Co-morbidity
•
•
•
•
•
Osteoarthritis
Obstructive sleep apnea
Diabetes
Cancer
Cardiovascular disease
Environmental Factors
• Overeating
– High caloric, “energy-dense” foods
– Fast food consumption tripled and calorie
intake quadrupled between 1977-1995 in North
America
• Sedentary lifestyle
Genetics
• Prader-Willi syndrome
– 7 gene deletion, chromosome 15q
• Bardet-Biedl syndrome
– 12 genes, chromosome 11 or 16
– BBS proteins
• MOMO syndrome
– Extremely rare (1 in 100 million births); seems to be autosomal dominant
mutation
• Leptin receptor mutations
– Regulates adipose-tissue mass
• Melanocortin receptor mutations
– G-protein coupled receptors; account for 6% of early-onset obesity
• Single-locus mutations only account for 7% of all
cases of obesity
Neurobiological Mechanisms
• Leptin
– Produced by adipose tissue
– Signals fat storage reserves in body
– Mediates long-term appetite controls (eat more when fat
stores low, less when stores are high)
• Ghrelin
– Produced by stomach
– Modulates short-term appetite control (eat when empty,
stop when stretched)
• Both produced peripherally, but act on CNS,
primarily hypothalamus
Hypothalamus
• Several circuits contribute to hypothalamus’
involvement in appetite
• Melanocortin pathway
– Arcuate nucleus (AN) --> lateral hypothalamus (LH)
and ventromedial hypothalamus (VMH)
• LH = brain’s feeding centre VMH = brain’s satiety centre
– When AN neurons activated --> appetite
– Neurons inhibited by circulating leptin and ghrelin
Leptin
• Leptin originally
discovered 1950s;
homozygous mutation -->
obese mice
• But, not the primary cause
of obesity in humans
• Over 240 other mouse
genes identified in weight
<wikipedia.org/wiki/Image:Fatmouse.jpg>
FTO
• Obesity risk allele
– 10 SNPs in first intron of FTO; chromosome 16
• About 39,000 Europeans studied (Frayling et al.
(2007))
• Versus individuals with no variant copy:
– One copy, average 1.2kg heavier; 30% increased risk of
obesity
– Two copies (16% of subjects), average 3kg heavier,
70% increased risk of obesity
• Ethnic differences in copy variant frequencies
– 45% West/Central Europeans; 52% West African; 14%
Chinese and Japanese
Addictions
• Typically, some form of chemical use
• Substance alters body physiology and/or
neurochemistry
– Recurring compulsion
• Questions about other addictions
– E.g., food, gambling, sex
– Suggestions that these may be components of obsessive
compulsive disorder, not addictions, per se
Alcoholism
• Runs in families
• 40% and 20% risk for first degree male and
female relatives of alcoholic proband, respectively
– 20% and 5% for general male and female population,
respectively
• Assortative mating for alcohol use high (0.38)
– Could be inflating shared environment estimates
Male Twin Studies
• Moderate heritability for males, modest for
females
• E.g., Concordances: MZ ~ 50%, DZ ~35%
• Heritability ~0.6
• Early onset and more severe alcoholism is
more heritable
Female Twin Studies
• Inconsistent results
• Heritability figures range from 0.25 to 0.55
Shared Environment
• Related to initial alcohol use in teens and young
adults, but not to later alcohol abuse
• Effect on siblings, not parents and offspring
• Correlation for alcohol abuse in parents and
biological teens 0.3, but only 0.04 for adopted
teens
• Correlation for alcohol abuse in unrelated adopted
siblings 0.24 (0.45 for same sex, 0.01 for opposite
sex)
• Sibling and/or peer effects more important than
parent effects in adolescence
Genotype-Environment
Interaction
• Genetic risk for alcoholism greater in more
permissive environments
• Heritability lower for:
–
–
–
–
Married individuals
People with strong religious upbringing
People from stricter and closer families
Regions with lower alcohol sales
Animal Models
• Long sleep (LS) and short sleep (SS) mice
• Inbred strain
• After 18 generations LS mice “slept” for
average of 2 hours post alcohol; SS mice
only for about 10 minutes
– Lot of variation in LS (1.2 - 4.4 hours); less in
SS (0 - 0.65 hours)
Alcohol Response Polygenic
• Suggests many genes involved
– Steady divergence over 18 generations (1 or 2 genes would
have stabilized much sooner)
– Variability in sleep times for LS and SS
– Different responses by LS & SS strains to other drugs
(e.g., cocaine, morphine)
• QTL mapping and knockout studies identify 5 genes
for dopamine D2 receptor
– Each gene accounts for 20 minutes of sleep; five about 130
minutes of total 170 minute difference between LS and SS
mice
• Dopamine D4 receptor knockout -->
supersensitivity to alcohol, cocaine,
methamphetamine
• Serotonin receptor knockout --> increased alcohol
consumption
Humans
• Ethnic differences
• Mutant ALDH2 allele
– Inactivates key enzyme in alcohol metabolism
– 25% Chinese, 40% Japanese, almost no
Caucasians
• But, this and other genes don’t show
consistent effects even within ethnic groups
Smoking
• MZ concordance, 75%
• DZ concordance, 63%
• Heritability about 60% with some shared
environmental effects
– Like alcohol, less parents, more peers and
siblings
Aging
• Tricky
• Older individuals vary greatly biologically
and psychologically
• So, grouping into “elderly” for analysis not
very effective
• Relatively little behavioural genetics work
on second half of lifespan
– Traditional nurturist/behaviourist carry-over?
Effects
• Specific types (e.g., Alzheimer’s)
• General cognitive decline
– Various tests, e.g., Informant Questionnaire on
Cognitive Decline in the Elderly (IQCODE)
• Differences in abilities
– Fluid abilities decline (e.g., spatial)
– Crystallized abilities improve (e.g., vocabulary)
– Both equally heritable
• Personality traits remarkably stable across
adult lifespan; large genetic effect here
• Heritabilities of late life psychopathology
and personality disorders very similar to
younger rates
• Longevity only has modest genetic effects
(heritability about 25%)