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Genetic Genetic DisordersDisorders

Gaia ScerifRoom 426, Ext. 67926

gs@psychology.nottingham.ac.ukOffice Hours: Thurs 1-3

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Learning objectivesLearning objectives

* Why study genetic Why study genetic disorders? disorders?

• Disorders following Disorders following Mendelian Laws of Mendelian Laws of InheritanceInheritance

• Beyond Mendelian LawsBeyond Mendelian Laws

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Why study genetic Why study genetic disorders?disorders?

Clinical Practice:Clinical Practice: The Human Genome Project has increased the

probability of identifying genetic origins for an increasing number of disorders previously defined solely in terms of their symptoms

Official site of the Human Genome Project:http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/diseaseindex.shtml

Online Mendelian Inheritance in Man (OMIM):http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

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Why study genetic Why study genetic disorders?disorders?

Theory:Theory: For a number of researchers, genetic disorders also provide a unique

opportunity:

Decreased or absent expression of a gene A, accompanied by a deficit in function B

=> Role of A in implementing B

The 21st century as the “dawn of cognitive geneticsdawn of cognitive genetics” (Pinker, 2001, p. 466)

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Disorders and Mendelian Disorders and Mendelian LawsLaws

Huntington’s Disease (HD): 1 in 10,000-20,000 individuals Characterised by involuntary movements, personality

changes, forgetfulness Due to progressive damage of basal ganglia and cortex

= Autosomal dominant disorder (chr. 4) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

Hh hhParents

HhHh HhHh hhhhOffspring

Gametes H h h h

AffectedAffected Unaffected

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Disorders and Mendelian Disorders and Mendelian LawsLaws

Phenylketonuria (PKU): 1 in 10,000 individuals Used to be responsible for 1% of all hospitalised cases of

learning disability Due to dysfunction in pathway producing the amino acid

tyrosine

= Autosomal recessive disorder (chr. 12)

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=261600

Pp PpParents

PP Pp ppppPpOffspring

Gametes P p P p

Unaffected

Carriers AffectedAffected

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Beyond MendelBeyond Mendel1. Sporadic mutations. For example: Abnormalities in chromosomal numbers Deletions (single genes, multiple genes)

2. X-linked disorders Changes in the number of X chromosomes Gene dysfunctions for single genes on the X

chromosome

3. Complex traits Schizophrenia?

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1. Sporadic Changes 1. Sporadic Changes Abnormalities in chromosomal numbers

(due to errors in segregation of alleles when gametes are produced)

E.g., Down’s syndrome: Approximately 1 in 1,000 Prevalence increases depending on age of parents Majority of cases due to trisomy of chromosome 21 Some symptoms (e.g., facial dysmorphology) evident

from birth, while others (short stature, learning difficulties) only become apparent later in life.

In general, IQ on average 55, but great variability in general performance and cognitive profile

http://www.downs-syndrome.org.uk/

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1. Sporadic Changes 1. Sporadic Changes Deletions (due to errors in replication of

DNA during gamete formation)

E.g., Williams syndrome: Approximately 1 in 20,000 Prevalence does not increase depending on age of

parents Due to a microdeletion on chromosome 7 Some symptoms (e.g., facial dysmorphology) In general, IQ on average 50-70, but great variability

in general performance and cognitive profile Uneven profile of cognitive abilities has been of great

interest: dissociation between language and general cognitive ability?

http://www.williams-syndrome.org.uk/

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2. X-linked Genes2. X-linked Genes Sex chromosomes are inherited differently for males (XY)

and females (XX), so detecting that a gene is located on the X chromosome is easier

Colour-blindness: first reported case of human X linkage:

cc C

c cC cC

c

CC c

CcC C Cc

CC c cC

C

C

FatherMother

Daughter Son

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2. X-linked Disorders2. X-linked Disorders Changes in the number of sex

chromosomes: X0 (women with Turner syndrome):

1 in 2,500 births Physical characteristics: E.g., Short stature, infertility Verbal IQ generally normal, but performance IQ can

be lower http://gslc.genetics.utah.edu/units/disorders/karyotype/turnersyndrome.cfm

http://www.tss.org.uk/

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2. X-linked Disorders2. X-linked Disorders Changes in the number of sex

chromosomes: X(+)XY (men with Kleinefelter syndrome):

1 in 750 male births Main problems due to hormonal imbalances

(treatable), lower than average IQ, speech and language difficulties http://klinefeltersyndrome.org/

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2. X-linked Disorders2. X-linked DisordersGene dysfunctions for single genes on the X

chromosome: Fragile X syndrome:

1 in 2000-4,000 boys, 1 in 6,000 girls Complex profile of relative cognitive strengths (e.g.,

receptive language) and difficulties (e.g., visuo-spatial cognition and attention)

http://www.fraxa.org/

http://www.fragilex.org.uk/page3.htm

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3. Complex Traits3. Complex Traits

For complex traits, a behaviour genetics approach is necessary. Twins as a way of testing whether shared genetic and environmental factors account for risk

Schizophrenia Nearly 1 in 100 people No simple inheritance pattern Familial (morbidity risk) Adoption studies:

5% rate of schizophrenia forbiological parents of schizophrenic adoptees

(Kety et al., 1994) Strong genetic influence, but…

0

5

10

15

20

25

30

35

40

45

50

Unrelated

(population

risk)

Second

degree (25%)

First degree

(50%)

Fraternal

Twins (50%)

Identical

twins (100%)

1%

9%

17%

48%

4%

Modified from Gottesman (1991)

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SummarySummary

* Why study genetic disorders? Why study genetic disorders? Practice and theoryPractice and theory

• Disorders following Mendelian Disorders following Mendelian lawslaws• Autosomal dominant (HD)Autosomal dominant (HD)• Autosomal recessive (PKU)Autosomal recessive (PKU)

• Beyond Mendelian LawsBeyond Mendelian Laws• Sporadic disorders (DS, WS)Sporadic disorders (DS, WS)• X-linked disorders (Turner, X-linked disorders (Turner,

Kleinefelter, Fragile X syndrome)Kleinefelter, Fragile X syndrome)• Complex traits (schizophrenia, Complex traits (schizophrenia,

mood disorders)mood disorders)