Professor Ian Craig

1
?? ????????????? ?????? ?
????????????? ????????? ??? ?????? ?? ????
? Professor Ian Craig ?????????
??? ????? Education Coummity
???????? ?? ??????????? Human Genome
Organisation, ?????????
??????????? HUGO
?? ???????? ??????
???????? Social Genetic and Developmental
Centre Institute of Psychiatry London
2
The early days at a mental asylum (Bethlem Royal
Hospital, London) ??????????? ???????? ?????? ?
???????
???? ?? ??????
??????????????? ???????
3
Behaviours that run in families ?????????????
???????? ???????????? ?? ???????? ??????

• Huntingtons disease
• Alzheimers disease
• Manic depression
• Schizophrenia
• Intelligence
• Moral beliefs

• ??????? ???????????
• ??????? ???????????
• ???????????? ?????????
• ??????????
• ?????????
• ????????? ?????????

4
??????????? ??????
??? ????????? ????????????? ???? ? 80 ??? ????,
??? ??? ????? ?????????, ?? ??? ????????
??????????? ??????? ???????

• Attending medical school
• the risk for first degree relatives is eighty
  times that for the general population
• But obviously not a simple genetic trait

5
Genetic Relationships and Risk of
Schizophrenia???????????? ??????? ? ????
??????????
????????????? ????
Second Degree ??????
First Degree????????-????
Unrelated ??????????????
Fraternal Twins????????????? ????????
Identical Twins ??????????? ????????
1 25 50
50 100
? ? ? ? ? ? ? ? ? ? ? ? ? ? ,
6
Careful comparison of the extent of similarity
between identical (monozygous) twins and between
fraternal (dizygous) twins allows an estimate of
the extent to which genetic factors rather than
environmental factors are responsible for
behaviours.
????????????? ???????? ????? ?????? ??????????
????????? ??????? ???????????? ?????????
????????? ??????? ??????? ??????? ???????????? ?
???????? ???????? ?? ??????????? ????????.
7
Amount of variation which is genetic
(heritability) for various traits ?????
???????????????? ? ???????????? ?????????
????????? ????????? 40-70 Depression
??????????? ???????/ ????????? 50
(?????????) Cognition/Intelligence
(adolescents) ?????????? 80 Schizophrenia
??????? ??????????????? 75 ?
?????????? ???????? Attention Deficit
Hyperactivity Disorder (ADHD)
8
The genetic contribution for most behaviours is
thought to come from many genes each with small
effect they are called Quantitative Trait Loci,
QTLs Each gene can have more than one form
(alleles) and an individual may have two
identical or two different versions of each gene
??????????????, ??? ??????????? ?????????????
????????? ??????? ?? ?????? ?????, ?????? ??
??????? ????????? ????????? ??????? ?? ???????.
????? ???? ?????????? ???????? ??????????????
????????? (???) ?????? ??? ????? ????? ?????
?????? ???????? (??????), ? ?????? ??????? ?????
????? ??? ?????????? ??? ??? ?????? ????????
??????? ????
9
Model of complex traitssuch as intelligence and
behaviours
????????????? ?????????????? ?????????, ?????
??? ????????? ? ?????????
Number of people with Given IQ ????? ????? ?
?????? IQ
???????? IQ
Low Mean 100

High Intelligence Scores
10
Model of complex traits such as intelligence and
behaviours????????????? ???????, ??????????????
??????? ???????? ????????? ? ?????????
?????? ??????????
high allele ??????? low
allele???????
Low extreme Population mean High
Extreme?????? ???????
? ?????????
??????? TRAIT SCORES
??????? ??????????
11
QTLs and complex traits ?????? ??????????????
????????? ? ???????????? ???????? ???????
?????????

QTL EFFECTS ????? ????????? ???????
Environmental Variance
Genetic variance
????? ????????????????
12
How do environment and genes interact?
??? ??????????????? ????? ? ?????
???????????? ??????? ??????????? ?????????
???????-???????????????????????
?????????? ??? ?????? II
???? A???? ???
??????? ????????? Poisoning
Asthma Type II diabetes Cancer PKU
Heart attack Depression
Cystic fibrosis Huntington Disease Haemophilia
Vehicle accidents
ENVIRONMENTAL
GENETIC'
?????
????
13
Gene Hunting for Behaviours ????? ?? ??????,
????????? ?? ????????? 1. ?????????????
???????????? ????????? ? ??????????? ???????? ?
????????????? - ?????? ????????? 1. Follow
behaviours and chromosome markers in families -
Linkage
14
Gene Hunting for Behaviours ????? ?? ??????,
????????? ?? ????????? 2. ???????? ????????
????????????? ??? ????? ??????? ????????? ?
?????? ????????? (???????) ? ??????? ?????????
????????? (????????) ?????? ??????????2.
Examine overall differences in chromosomal DNA
patterns between groups of affected individuals
(cases) and normal individuals (controls)
Association
15
The Human Genome Project has provided an amazing
array of markers across all of the chromosomes
and allowed us to choose specific candidate
genes to study behaviours. The next few slides
remind us of the sorts of DNA markers available
and the genes that might be particularly worth
examining in context of behavioural
disorders. ?????? ????? ???????? ???????????
???????? ?????????? ???????? ?? ???? ?????????? ?
???????? ??? ???????? ?????????? ????-?????????
??? ???????? ????????????? ?????????. ?????????
????????? ??????? ????????? ???? ????????????
???????? ??? ? ???? ?????????, ??????????? ?
????????? ????????????? ???????????.
16
The Nature of DNA markersSNPs (Single
Nucleotide Polymorphisms) Single base pair
substitutions Generally two versions
(alleles) for each gene Probably stable and
ancient Every few hundred base pairs gt c. 2
million /genome ???? ???????? ???
???????????????? ???????????? (SNPs) ??????
?????? ?????????? ???????????? ????? ????????
(??????) ??????? ???? ????????, ?????????? ?
??????? ??????????? 1/1000 ??????????? ????? gt
7-10 ????????? SNPs ? ??????? ?????
17
The Nature of DNA markersSSRs (Simple sequence
repeats (microsatellites) Most common are
dinucleotide repeats e.g. (ACACACACACACetc )
but also repeating motifs of three, four and
more bases. Highly variable About 1,000,000
per genome ???? ???????? ??? SSRs ???????
??????? (??????????????) ????? ????????????????
?????????????? ???????, ????????
(ACACACACACAC), ? ????? ??? ? ?????????????????
???????. ??????? ?????????????? (?????????
???????) ????? 1,000,000 ??
?????
18
I intend to show how genes involved in neurone
activity in the brain can effect behaviours such
as Antisocial Behaviour/Aggression Depression
And, if time Attention Deficit Hyperactivity
(ADHD) ? ??????, ??? ????, ??????????? ? ??????
??????? ?????? ?????, ????? ?????? ?? ????? ?????
????????? ??? ?????????????? ?????????/????????
????????? ? (???? ???????? ?????)

??????? ??????????????? ? ????????? ????????
19
Serotonin (5-HT)
Serotonin Transporter (SERT)
??????????? ?????????? (SERT)
????????? (5-HT)
??????????? ?????????? (???????????????? A, MAOA)
????????????????? ?????????
?????? ??????? ?????? ?????
20
The dopamine neurone is similar
???????? ??????? ? ??????? ? ??????? ????????
?????????? ??????? ???????
Postsynaptic Neurone Receptors are stimulated by
dopamine ????????????????? ?????? ???????
??????????? ????????? ???????
Presynaptic Neurone makes and releases Dopamine ??
?????????????? ?????? ?????????? ? ???????????
???????
reuptake ???????? ??????????
??????? Dopamine
21
Many genes involved in controlling dopamine and
serotonin mediated transmission in the brain can
have different forms Some versions work better
than others!?????? ????, ?????????????? ??????
???????? ? ??????????, ?.?. ???????? ???????
????????? ? ?????, ???????????? ???????
?????????? (????????) ???? ???????? ?????
?????????????, ??? ??????!
22
Different individuals can have different
combinations of the gene versionse.g. High//High
High//Low Low//Low ?????? ????
????? ????? ?????? ????????? ????????? ?????,
???????????? ???????????????? ??????????
???????? ???????/???????
???????/?????? ??????/??????
23
Both serotonin (5-HT) and dopamine are involved
in a wide range of functions, e.g. motor control,
emotion, learning, reward mechanisms and memory
??? ?????????, ??? ? ??????? ????????? ? ???????
???? ???????, ???????? ???????? ????????,
??????, ????????, ????????? ?????????????? ?
??????
24
We chose to look at three genes involved in
behaviour in a longitudinal study of about 1,000
individualsMonoamine oxidase, Serotonin
Transporter and Tyrosine hydroxylase
?? ??????? ??? ???? ??? ???????? ?
??????????????? ???????????? ???????? 1000
??????? ????????????????,
??????????? ??????????, ???????
????????????
25
The Dunedin Multidisciplinary Health and
Development Study

• All individuals born in Dunedin, NZ, April 1st
  1972 March 31st 1973
• ??? ????, ????????? ? ????????, ????? ????????, ?
  1-?? ?????? 1972 ?? 31-? ????? 1973
• Examined at birth and then at ages
  3,5,7,9,11,13,15,18 and 26.
• ??????????? ????? ????? ???????? ? ????? ?
  ???????? 3,5,7,9,11,13,15,18 ? 26 ???.
• DNA collected ???????????????? ?? ???

26
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27
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Analysis Phase I ?????? ???? I

• Antisocial behavior and Monoamine Oxidase A
• ?????????????? ????????? ? ???????????????? A

29
Evidence for involvement of MAOA in antisocial
behavior

• Defective gene in a Dutch Family

• ??????, ?????????????? ??????? MAOA ?
  ?????????????? ?????????
• ????????? ??? ? ??????????? ?????

30
Affected males have a mutation in their MAOA gene
which prevents it working MAOA gene is on the
X-chromosome and males only have one copy ?
??????? ?????? ??????? ???????, ???????????- ???
??? MAOA ??? MAOA ????????? ?? ????????? X ?
?????? ?????? ???? ?????
Affected males show antisocial behaviour, commit
arson and inappropriate sexual contacts with
family members. ??????? ??????? ?????????????
?????????????? ?????????, ????? ??? ???????
??????? ? ???????????? ??????????? ????????? ?
??????? ?????
31
More evidence for involvement of MAOA in
antisocial behavior?????????????? ?????????????
??????? ???? ???????????????? ?? ??????????????
?????????

• Gene Knocked Out in Mice (Cases et al 1995)
• ?????? ?????? ? ?????

Video courtesy of Frans Schluyter
?? ????? ?????? ???? ???????? ? ???????????
????????? ????? ?????
32
The monoamine oxidase A gene, MAOA
??? ???????????????? A, MAOA
3
5
Coding regions ?????-??????????
??????? 90,000 ??? ???????????
???????? (???????????? ?????????? ????)
Promoter region (controls gene activity)
30 ???????????? ?????? (VNTR) 3 ????? (???????
??????????) 4 ????? (?????? ??????????)
????????
30 bp repeat (VNTR) 3 copies (low activity) 4
copies (high activity))
33
?????? ????????? MAOA
34
???? ???????? MAOA ? ??????????? ?????????
?????, ???????? ? ??????????????? ????????
35
Exposure to childhood maltreatment as a function
of MAOA activity
??????????????? ??????? ? ??????? ?
????????????? ?????????? ???? MAOA
70
?????? ?????????? Low activity ???????
?????????? High activity
60
50
40
of study members
30
20
10
0
None ???
Probable ????????
Severe???????????
Childhood maltreatment
??????????????? ??????? ? ???????
36
MAOA promoter VNTR allele and conviction of a
violent crime
VNTR ?????? ????????? MAOA ? ???????? ??
?????????? ????????????
1 conviction, n 45
No conviction, n 397 ??? ?????????
MAOA Gene type
gt1 ?????????
18 (40)
145 (37)
Low ?????? activity ??????????
27 (60)
252 (63)
High ??????? activity ??????????
??? ???????????? ???????
No significant differences
37
MAOA and antisocial behavior interaction
between a gene and stress
MAOA ? ?????????????? ?????????
?????????????? ????? ?????? ? ????????

• Childhood maltreatment is a well-documented
  environmental risk for adult antisocial behavior
• ?????? ????????? ? ??????? - ????????? ????????
  ?????? ????? ??????????????? ?????????
• Assessment of - ???
• Physical abuse ????????
• Sexual abuse ??????????? ???????
• Change of primary care-giver ????? ????????
• Harsh discipline ??????? ??????????
• Rejecting mother ????, ??????????? ???????

38
Childhood maltreatment(ages 3-11 years)
??????????????? ??????? ? ??????? (3-11 ???)

• Observations of mothers behaviour (age 3)
• Parental reports of harsh discipline (ages 7-9)
• Multiple caregiver changes (through age 11)
• Physical harm (retrospective report)
• Unwanted sexual contact (retrospective report)
• ?????????? ?? ?????????? ?????? (3 ???)
• ????????? ????????? ? ??????? ?????????? (7-9
  ???)
• ?????????? ????????? (???????????????
  ?????????????)
• ?????????????? ??????????? ???????
  (??????????????? ?????????????)

39
Childhood maltreatment(ages 3 -11 years)
??????????????? ??????? ? ??????? (??????? 3 -11
???)

• For each Study child, we derived a cumulative
  exposure index by summing the number of
  maltreatment experiences reported during the
  first decade of life.

Maltreatment
????????? ??????? -gt
40
MAOA, childhood maltreatment and personality
disposition towards violenceThe disposition
toward violence at high maltreatment is higher if
MAOA activity is low Interaction (b -0.24, SE
0.15, t 1.62, p 0.10)??????????????????? ?
???????? ????? ??????????????? ??????? ? ???????
???? ??? ?????? ?????????? ???? ????
??????????????? ?????????????????????????
??????????????????? ? ????????
?????????? ???? ???? ?????? ???????
41
MAOA, childhood maltreatment and Conduct
Disorder MAOA, ??????????????? ??????? ? ???????
? ????????? ?????????
Interaction (b -0.63, SE 0.33, z 1.87, p
0.06)
42
Conviction of a violent crime by age 26
???????? ???????? ?? ????????? ???????????? ? 26
?????

• Court records searched for all Study members
• 25 of Study males received 987 criminal
  convictions
• 11 of Study males received 172 convictions for
  violent crimes
• ????? ????????????? ??????
• 25 ???????? 987 ??????????
• 11 ? ???????? 172 ????????? ?? ?????????
  ????????????

• Common assault
• Assault with intent to injure
• Manslaughter
• Rape
• Indecent assault on female
• Aggravated cruelty to animal

• ?????????
• ????????? ? ????? ????????? ???????????
• ????????
• ?????????????
• ????????? ?? ???????
• ?????????? ?? ????????? ? ????????

43
?????????? ???? ?????? ???????
?????? ??????????????? ?????????
?????? ????????? ? ??????? ??? ????
???????????
44
Conclusions
??????????

• The high activity version of the monoamine
  oxidase gene (MAOA) protects males against
  abusive childhood outcomes. Males with the low
  activity form are more likely to be aggressive
  and violent if they experience adverse early life
  events. Such important conclusions require
  confirmation

• ??????-???????? ??????? ???? ????????????????
  (MAOA) ???????? ????? ???????? ???? ??
  ??????????? ??????????????? ??????? ? ???????. ?
  ????? ???????? ???? ? ?????-???????? ?????????
  ?????? ??????????? ????? ????????????, ???? ???
  ???????? ??????????????? ??????? ? ???????.
• ??? ?????? ?????? ????????? ? ?????????????

45
Archives of General Psychiatry July 2004
46
 
 
47
(No Transcript)
48
(??????? ????)
MAOA Gene Promoter Variation and Rearing
Experience Influences Aggressive Behavior in
Rhesus Monkeys ???????? ?????????? ????????? ????
???? ? ?????????????? ???? ?????? ??
??????????? ????????? ? ????? ?????   Timothy K.
Newman1, Yana Syagailo2, Christina S. Barr1, Jens
Wendland2, Maribeth Champoux3, Markus Graessle2,
Stephen J. Suomi3,4_at_, J. Dee Higley1,4_at_,
Klaus-Peter Lesch2,5_at_ _at_ The laboratories of the
last three authors contributed equally and
authorship order should be considered
interchangeable.  Biol Psych In Press
49
???????? ?? ????? ???????
???????, ?????????????? ?????? ???? ????
50
(No Transcript)
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??????? ???????/ ?????? ? ???????/ ????????
???????
??????? ????????????/ ?????? ?? ????????????/
???????? ????????????
52
?? ????? ??? ???????????? ???????? !!
53
Influence of Life Stress onDepression
Moderation by variation in the Serotonin
Transporter Gene
Analysis Phase II
??????? ????????? ???????? ?? ????????? ???????
???????? ? ???? ???????????? ??????????
54
What is the relationship between stressful life
events and depression?
?????? ??????????????? ????? ???????????
????????? ? ???????????

• Stressful Life Events (SLEs) are known to
  influence the onset and course of depression
• But, not all individuals who experience SLEs
  succumb to a depressive episode
• ????????, ??? ????????? ?????? ?????? ??
  ???????? ?????????
• ?? ?? ? ???? ?????, ?????????? ??????????
  ???????? , ?????????? ?????????.

55
Serotonin (5-HT)
Serotonin Transporter (5-HTT)
??????????? ?????????? (SERT)
????????? (5HT)
?????? ??????? ?????? ?????
56
The serotonin transporter gene
??? ???????????? ??????????
(?????? ??????????)
(??????? ??????????)
From Lesch and MÖssner Biol. Psychiatry, 1998
57

• The serotonin transporter (SERT) has been linked
  to stress response and anxiety in various
  studies
• ??????? ?????? ?????????? ????????????,
  ??????????? ??????????? ?????????? (SERT) ?
  ???????? ?? ??????? ? ????????? ??????????
• mice with defective SERT gene respond very
  anxiously to stress (Murphy et al, Brain Res.
  Bull., 2001)
• Rhesus macaques with low activity gene show
  increased sensitivity to stress in rearing
  environment (Bennett et al, Mol. Psychiatry,
  2002)
• ???? ? ??????????? SERT ????? ????????? ?? ??????
  ? ?????????? ????????????
• ?????? ????? ? ?????-???????? ????? ?????????????
  ?????????? ???????????????? ? ??????? ? ?????,
  ??? ??? ??????

58
The association between Stressful Life Events and
self-reports of depression symptoms at age 26, as
a function of SERT genotype ?????????? ?????
???????? ?????????? ??????? ? ????????
???????????? ????????? ? ???????? 26 ??? ?
??????????? ?? ???????? SERT
?????-???????? ??? (2 ?????)
??????????? ?????????
Self reports of depression symptoms, age 26
??????-???????? ??? (2 ?????)
5-HTT gene
Five groups of individuals having different
numbers of life events, ages 21-26
??????????????? ????? ?????????? ??????? ?
???????? 21-26 -gt
59
The association between Stressful Life Events and
suicide attempt/ideation at age 26, as a function
of 5-HTTLPR genotype ?????????? ????? ????????
?????????? ??????? ? ???????? ???????/????????????
? ??????? ? ???????? 26 ??? ? ??????????? ??
???????? SERT
?????-???????? ??? (2 ?????)
Probability of suicide ideation/attempt, age 26
5-HTT gene
??????????? ??????? ????????????
??????-???????? ??? (2 ?????)
Five groups of individuals having different
numbers of life events, ages 21-26
??????????????? ????? ?????????? ??????? ?
???????? 21-26 -gt
60
The association between childhood maltreatment
and adult depression, as a function of
SERT ??????????? ????? ???????????????? ?????????
? ??????? ? ?????????? ?? ???????? ????????, ???
??????? SERT
?????-???????? ??? (2 ?????)
??????-???????? ??? (2 ?????)
??????????? ????????????? ??????? ? ????????
17-26
5-HTT gene
Probability of major depression episode, ages
17-26
Three groups of childhood maltreatment, ages 3-11
????????? ??????? -gt
61
SERT gene Conclusions

• ?????? ???????? ???? SERT ? ???????? ? ?????????
  ? ????????? ???????? ????????? ?????????????
  ?????????? ? ?????????
• ??????? ???? SERT ?? ??????????? ?????????????
  ????????? ???????????? ? ??????? ???? ?????
• The SERT gene interacts with Stressful Life
  Events (SLEs) to predict susceptibility to
  depression
• Interaction is specific for SERT and depressive
  outcome, and persists across the life course.

62
Replication
?????????????
PNAS Nov/Dec 2004
63
Replication in Rhesus Macaques
????????????? ?? ??????? ?????
????????????????? ??????? ?? ???????????????
????????? ? ??????? ? ????????? ????????? ????
???????????? ?????????? ? ????? ?????
Proc Nat Acad Sci USA 101 12358-12363 Aug 2004
64
Overall Conclusions

• ??????? ?? ????? ???????? ????, ????????
  ???????????? ???? ? ???????????? ???
  ????????????, ??? ? ????????????? ?????????.
  ?????? ?? ??????? ???????? ?????? ??? ?????
  ????????? ???????
• ???????????, ??? ???????? ????? ???????????? ?
  ????????, ??????????? ?????????? ? ? ??????
  ????????
• We can now identify genes which can play a
  significant role in determining both aggressive
  and depressive behaviours. However, their effects
  can only be easily seen if life events are taken
  into consideration
• Amazingly, the forms of the genes seen in humans
  appear to have counterparts in other primates
  (Rhesus macaques).

65
And Joseph McClay (who was always late for lab
meetings)