(UAB+HA) = MOVE_TO_ALABAMA

(UAB+HA) = MOVE_TO_ALABAMA Hudson river Short drive to daughter in NY Heaven on earth condo Tenured, 100% hard money (UAB+HA) = 30 year goal cut to 15 years
GOAL 1.  EffecBve treatment based on genotype 2.  Simple prevenBon strategies based on genotype UAB: CLINICAL RESOURCES & EXPERTISE HA: GENOMICS RESOURCES & EXPERTISE What we are studying now 1. 
2. 
3. 
4. 
Genes that increase/reduce risk of PD Genes that accelerate/delay age at onset Role of gut microbiome on PD Gene–environment / gene-­‐drug interacBon NGRC Clinics/Data collecBon sites NGRC
NeuroGene8cs Research Consor8um BHAM N= 2000 persons with PD, 2000 controls 2000, 2000 projected for UAB GeneBc data •  genomewide: 7,000,000 genotypes / subject Life-­‐Bme environmental exposure data •  Smoking •  Caffeine •  Non-­‐steroidal anB-­‐inflammatory drugs (NSAID) Gut microbiome 1. Genes that increase or reduce risk of PD What causes PD? Can it be prevented? What are the genes that affect risk How do environmental factors play in? (epigene8cs) Can preven8on be as simple as iden8fying at risk individuals, and based on genotype, telling them what to do or what to avoid? 2,000 PD cases 2,000 controls Payami et al Nat Genet HLA 2010 UPDATE: PD is associated with HLA Class II and Class I. PD variants are associated with expression levels of HLA Class I and Class II genes Tansey et al showed rs3129882_G is associates with higher expression of class II genes, and when cells are stressed, PD cells with G allele show dramaBc increase in class II expression 1500000 Reduced T cell in blood of PD CNV case 22000000 22500000 23000000 23500000 cont 24000000
1. COLLABORATIONS •  I would like to be part of STANDAERT Neurology UAB next proposal for innate and adapBve immunity in PD •  I would like to collaborate with Jian Han @ HA on immune repertoire of PD •  I would like to collaborate with anyone who can help me study HLA gene regulaBon and PD •  I would like to collaborate genome-­‐wide gene expression and PD 2. Why do some people develop PD in their 20’s, 30’s and 40’s and others not unBl their 80’s If age-­‐at-­‐onset can be delayed by a few years, a significant number of cases may never occur, and among those who develop PD, fewer will experience physical disability, demenBa and psychosis as disease progresses •  Genes were predicted to have a bigger impact on age at onset than on risk. •  Yet 28 genes are confirmed for risk, none for age at onset LETTERS
14,000 PD cases 95,000 controls TX
1B
D
K
-S
P
T
B
C
K
R
IT
S 2
P
P
L
D 2B
D
R
G
K
1
VP
S
13
C
22
9B
M
A
G
C
H
1
EM
TM
P
5F
D
LG
M 2
IR
LR469
R 7
C K2
C
D
C
62
IN
P
B
N
M
G
P
–D
Q
B
1
H
LA
G
B
A
R
-S
A
YT
B
IP
7
11
A L
1L 1
2 N
U
C
A
K
C
S
1
S MS
TK D
39 -TM
EM
16
3
S
–log10 (P value)
K
M R
T C T
B M C 8P
FA S E C 25
M T1 M1 1 -A
P
75
4
O
S 7E
-G
O
N -S
P
A
C C
2
K
A A
D
R
G
B
K
2
Q
To identify
ated loci were
Nalls, Payami et al Nat Genet 28 loci 2014 attempted to r
80
pendent samp
60
genotyping ar
typed the >24
40
on the Illum
BeadChip an
20
ants proven o
0
in neurodege
2
3
4
5
6
7
8
9
10
11
12 13 14 15
17
19 21
1
D.G.H., M.F.K
Chromosome
lished data). W
Figure 1 Manhattan plot of discovery-phase meta-analyses. Black font denotes replicated loci from
included the 2
the discovery phase, and gray font denotes loci that did not replicate.
didate loci im
from the prim
independent
locus,
the
most
significan
disease in the discovery phase, on the basis of a widely accepted
−8
of proxy variants were included in th
genome-wide P-value threshold of 5 × 10 (Fig. 1 and Table 1;
quality control, high-quality genotype
additional details are provided in Supplementary Fig. 1 and
24
ple set of 5,353 cases and 5,551 contro
Supplementary Table 2) .
•  28 risk genes, collecBvely, affect age at onset by 37 days (InternaBonal PD ConsorBum 2015) Table 1 Results of discovery and replication association analyses
Discovery phase
(13,728 cases and
95,282 controls)
Replicat
(5,353
5,551
OR
OR
•  80 years (minus a month) of variaBon in age at onset is unexplained SNP information
SNP
Chr.
Position (bp)
Nearest gene(s)
Effect Alternate Effect allele
allele
allele
frequency
P
Genome-wide significant, discovery phase
a
−23
NGRC REPLICATION Age-­‐at-­‐
onset modifiers have Low allele Freq. MAF < 0.02 & Large effect 8 yr earlier onset 2. CollaboraBons Whole Genome Sequencing for uncommon/rare variants affecBng age at onset of PD •  Dataset 1: ExisBng NGRC •  Dataset 2: UAB •  Neurology UAB: paBents + clinical data + blood •  CCTS UAB: DNA isolaBon •  GSL HA: Whole genome sequencing •  Tiwary UAB + Absher HA + Payami UAB/HA : data analysis 3. GUT MICROBIOME OUR OTHER BRAIN Possible spreading of synucleinopathy from the enteric nervous system to the brain. PMID: 22544647 A pilot study with 200 cases 150 controls nearly completed in collaboraBon with Robb Knight Full-­‐blown study with 2000 PD, 2000 Controls about to start at UAB New CollaboraBons Study “PD microbiome” in gnotobioBc animals 4. gene-­‐environment (gene-­‐drug) interacBon studies Environmental factors & PD •  Paraquat and rotenone (herbicide/pesBcide) increase PD risk 2-­‐3 fold •  Caffeine •  cigarere smoking •  non-­‐steroidal anB-­‐inflammatory drugs NSAIDs each reduce PD risk 20%-­‐30% SLIGHT PROBLEM §  Smoking is more likely to kill you before it can protect you against PD §  Caffeine can cause anxiety, insomnia. Overdose can be fatal. §  NSAIDs can cause kidney failure, liver failure, ulcers. Harness the benefit, avoid the harm Lets find the genes that modulate the “protec8ve” effect of these drugs 1. Insight to disease pathways 2. Predict who would benefit from which drug. 4. genome-­‐wide gene-­‐environment (gene-­‐drug) interacBon studies Hypothesis-free
Data are generated by the grace of statistics.
if lucky to get a P=5e-8,
it can be anywhere in the genome
iden8fica8ons of genes that influence neuroprotec8ve effects of caffeine, nico8ne and ibuprofin 1.  GRIN2A glutamate receptor 2.  MAPK10
JNK3 brain specific stress induce apoptosis pathway 3.  SV2C substanIa nigra specific synapIc vesicle protein 4.  Long non-­‐coding RNA RELEVANCE TO PERSONALIZED TREATMENT & PREVENTION Risk reduc8on by caffeine use RELEVANCE TO PERSONALIZED TREATMENT & PREVENTION 1.  Treatment. Incorporated in on-­‐going trials of caffeine and nicoBne to validate genotype-­‐specific drug response 2.  PrevenBon Develop genotype-­‐based algorithms to match prevenBon strategy to the individual. Need Help/Collaborators Online longitudinal observaBonal trial