AGTCTCGATATCGATCCTCGCTCGACAGATCGA
AGTCTCGATATCGAACCTCGCTCGACAGATCGA
AGTCTCGATATCGAACGAACCTCGCTCGACAGATCGA
AGTCTCGATATCCTCGCTCGACAGATCGA
“snps”
“insertions, duplications”
“deletions”
STR Y-chr LOCUS #DYS393 14DYS19 14DYS391 10DYS439 10DYS389-1 12DYS389-2 17DYS388 12DYS390 22DYS426 11DYS385a 15DYS385b 16DYS392 11
HAPLOTYPE “G”Saudi Arabia, Iraq, Iran, Pakistan
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)
-80
-50
DRD2 activation suppressesCells in the resting state
DRD1 activation excitesCells in the -50 mV state
Coincident inputsWill drive a cell from -50 to -80 mV
ACTION POTENTIALS& SYNAPTICPLASTICITY
Can we deploy genetic markers as non-invasive proxies for mechanisms ?
word color
response
BLUE
NMDA
COMT DA
“gain”
+ *
+
+
+
+
D1= 400-1600 ms
400 ms
RT < 1700 ms
3500 - RT - D1 ms
100 ms
cue
target
Human Attention Network Task (ANT)
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”duringincongruent trials
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 OrientingConflict RT_____________________________________________h2
F = 2 (rMZ – r DZ) .18 -.59 .89 .16h2
H = (rMZ – r DZ)/ .14 -.49 .62 .24 (1 – r DZ)ML fit:h2 .18 .00 .72 .16
ᆬAlerting networkᆬOrienting networkᆬExecutive control networkᆬAlerting networkᆬOrienting networkᆬExecutive control network
Fan et al., 2004
Low DA levels High DA levels
2030N =
VAR00002
2.001.00
Me
an +
- 1
SE
VA
R00
001
.24
.22
.20
.18
.16
.14
.12Co
nflic
t rat
io s
core
COMT Val 108/158MAOA long prom. repeat
COMT Met 108/158MAOA short prom. repeat
MAOA (4-repeat) – (3-repeat)
4-repeat, LOW MA
3-repeat, Hi MA
Rea
ctio
n T
ime
Dif
f
Red = activity biased by MAOA 4-repeat allele
Blue = activity biased by MAOA 3-repeat allele
Fan et al., 2003
Julie Williams and Michael C O’DonovanEuropean Journal of Human Genetics (2006) 14, 681–689
DYX1C1DCDC2
KIAA0319