Human Linkage Studies of Psychiatric Illness

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Human Linkage Studies of Psychiatric Illness
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Extreme Discordant And Concordant Sib Pair Design
Both Siblings in Top 10
Both Siblings in Bottom 10
One Sibling in Top and one in Bottom 10
Risch and Zhang, Science, 2681584, 1995
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Neuroticism
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Neuroticism(N)

• N is a strong predictor of the onset of depression

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Neuroticism(N)

• N is a strong predictor of the onset of
  depression
• N is subject to genetic effects that are shared
  with depression

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Vicissitudes of Large Scale Studies
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Address Labels
Dr Jonathan Flint University of Oxford PO BOX
321 Rotherham Yorkshire
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EPQ Responses
Female
52,249
Male
35,892
TOTAL
88,141
Siblings
Female
16,186
Male
10,613
SIBLING PAIRS 34,000
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Total Sample
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The Neurotic Family Receives a DNA Swab Request
From Dr Flint
I have just received your request to send a
mouth swab. This is the last straw. My holiday
has just been cancelled, my son has influenza and
my husband has left me. Now this from you! It is
the END!
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Selected Sample
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Mapping Results

• Complete genome scan (LMS2 marker set 396
  markers)
• 500 families

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How To Analyze The Data
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Regression analysis

• Use information from squared differences and sums
  of sibling phenotypes (Visscher and Hopper Ann
  Hum Genet 65583)

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Regression analysis
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Visscher-Hopper Regression
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Genome-wide significance thresholds

• Simulate 10,000 data sets with the same allele
  frequencies, linkage, missing data, and family
  structure
• (SIMULATE Terwilliger, Genet Epidem 10217,
  1993 and MERLIN Abecasis, Nat Genet 3097, 2002)

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Genome-wide significance thresholds

• Five percent threshold 3.8
• One percent threshold 4.7

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Visscher-Hopper Regression
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Gender Effects
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Gender Effects
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Sex specific heritability of N
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Male and Female Pairs
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QTL on Mouse Chromosome One(Fearfulness)
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Mouse Human Homology
Human 1q
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Rat Fearfulness
Rat Chromosome 5
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Rat Human
Human 1p
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Synteny?
Rat
Mouse
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Summary

• Genetic effects on neuroticism can be found using
  an extreme discordant and concordant pair design
• Loci on chromosomes 1, 4, 7, 8, 11 and 12
• Sex specific effects
• Syntenic with rodent loci