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Human Linkage Studies of Psychiatric Illness

Human Linkage Studies of Psychiatric Illness. Extreme Discordant And Concordant Sib Pair Design. Both Sibli n gs in Top 10%. Both Siblings in Bottom 10%. One Sibling in Top and one in Bottom 10%. Risch and Zhang, Science, 268:1584, 1995. Neuroticism. Neuroticism (N).

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Human Linkage Studies of Psychiatric Illness

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  1. Human Linkage Studies of Psychiatric Illness

  2. 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, 268:1584, 1995

  3. Neuroticism

  4. Neuroticism(N) • N is a strong predictor of the onset of depression

  5. Neuroticism(N) • N is a strong predictor of the onset of depression • N is subject to genetic effects that are shared with depression

  6. Vicissitudes of Large Scale Studies

  7. Address Labels Dr Jonathan Flint University of Oxford PO BOX 321 Rotherham Yorkshire

  8. EPQ Responses Female 52,249 Male 35,892 TOTAL 88,141 Siblings Female 16,186 Male 10,613 SIBLING PAIRS: 34,000

  9. Total Sample

  10. 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!”

  11. Selected Sample

  12. Mapping Results • Complete genome scan (LMS2 marker set: 396 markers) • 500 families

  13. How To Analyze The Data

  14. Regression analysis • Use information from squared differences and sums of sibling phenotypes (Visscher and Hopper Ann Hum Genet 65:583)

  15. Regression analysis

  16. Visscher-Hopper Regression

  17. Genome-wide significance thresholds • Simulate 10,000 data sets with the same allele frequencies, linkage, missing data, and family structure (SIMULATE – Terwilliger, Genet Epidem 10:217, 1993 and MERLIN – Abecasis, Nat Genet 30:97, 2002)

  18. Genome-wide significance thresholds • Five percent threshold: 3.8 • One percent threshold: 4.7

  19. Visscher-Hopper Regression

  20. Gender Effects

  21. Gender Effects

  22. Sex specific heritability of N

  23. Female Pairs Male Pairs Male and Female Pairs

  24. QTL on Mouse Chromosome One(Fearfulness)

  25. Mouse Human Homology Human 1q

  26. Rat Fearfulness Rat Chromosome 5

  27. Chr Rat Human cRay HUMAN RAT (HSA) 0 12 37 119 RNO5 HSA9 9q22.3-q31 119 RNO5 HSA9 9q32 156 185 223 260 286 RNO5 308 RNO5 HSA1 1p31 323 * 359 * 385 * 394 RNO5 HSA1 chr.1 426 * 443 RNO5 HSA1 1p35-p31.3 443 RNO5 HSA1 1p35-p34 458 * 470 * 497 * 514 RNO5 HSA1 1p36-q12 520 * 556 RNO5 HSA1 1p33 596 RNO5 HSA1 1p36.2-p35 596 RNO5 HSA1 1p36.1-1p34.3 620 RNO5 HSA1 1p36.1-p35 630 RNO5 HSA1 1p36.1 630 RNO5 HSA1 1p35-p34 639 RNO5 HSA1 1p36.3-34.4 652 RNO5 HSA1 1p35 666 * 682 * 694 * 717 * 746 RNO5 HSA1 1p36.2 794 RNO5 HSA1 1p36.2 818 RNO5 HSA1 1p36.3 840 RNO5 HSA1 1p36.3 859 * 881 RNO5 HSA1 1p36.3-p32 Human 1p

  28. Synteny? Rat Mouse

  29. 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

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