7. The “real difficulty” in understanding genetic risk factors Sizing up human height variation by Peter M Visscher Genome-wide association studies have identified many variants affecting susceptibility to disease. Now, three studies use this approach to study adult height variation in a combined sample size of approx 63,000 individuals and report a total of 54 validated variants influencing this trait. Nature Genetics 40, 489 - 490 (2008)
8. Can we deploy genetic markers as non-invasive proxies for mechanisms ? “ gain” -80 -50 DRD2 activation suppresses Cells in the resting state DRD1 activation excites Cells in the -50 mV state Coincident inputs Will drive a cell from -50 to -80 mV ACTION POTENTIALS & SYNAPTIC PLASTICITY word color response BLUE NMDA COMT DA
10. Distribution of normalized scores for executive attention N = 200 normal adult volunteers Stimulus-Response conflict score 0 10 20 30 40 50 60 70 80 90 0.05 0.15 0.25 0.35 This group “ Slows down” during incongruent trials
11. Correlation values between twin pairs of MZ and DZ twins for each network and mean RT. _______________________________________ Twin Alerting Orienting Conflict RT _______________________________________ MZ .465 * .099 .727 ** .740 ** DZ .375 .395 * .281 .659 ** _______________________________________ Note: * p < .05; ** p < .01 Heritability Alerting Orienting Conflict RT _____________________________________________ h 2 F = 2 ( r MZ – r DZ ) .18 -.59 .89 .16 h 2 H = ( r MZ – r DZ )/ .14 -.49 .62 .24 (1 – r DZ ) ML fit: h 2 .18 .00 .72 .16
14. Low DA levels High DA levels 20 30 N = VAR00002 2.00 1.00 Mean +- 1 SE VAR00001 .24 .22 .20 .18 .16 .14 .12 Conflict ratio score COMT Val 108/158 MAOA long prom. repeat COMT Met 108/158 MAOA short prom. repeat
15. Fan et al., 2003 MAOA (4-repeat) – (3-repeat) 4-repeat, LOW MA 3-repeat, Hi MA Reaction Time Diff Red = activity biased by MAOA 4-repeat allele Blue = activity biased by MAOA 3-repeat allele
16. Julie Williams and Michael C O’Donovan European Journal of Human Genetics (2006) 14, 681–689 DYX1C1 DCDC2 KIAA0319