gene$c&varia$on&influences&the& severity&of&mul$ple...
TRANSCRIPT
Gene$c&varia$on&influences&the&severity&of&mul$ple&phenotypes&in&
Parkinson’s&Disease&
Stephanie&Millin&Webber&Group&
University&of&Oxford&
Contact:&[email protected]&
Phenotypic&variability&in&Parkinson’s&Disease&
Motor&phenotypes:&• Tremor&
• Bradykinesia&• Rigidity&and&
freezing&• Posture&and&gait&
Neurological&phenotypes:&
• Anxiety&• Depression&
• Cogni$ve&decline&
Autonomic&phenotypes:&• Sleep&disturbance&
• Smell&loss&• Cons$pa$on&&
• Response&to&medica$on&
Concept:&moving&from&discrete&to&con$nuous&phenotypes&
Phenotype&1&
Phenotype&1&
Phen
otype&2&
Phen
otype&2&
Phenotype&1&
Phenotype&1&
Phen
otype&2&
Phen
otype&2&
Phenotype&measures&in&the&Oxford&Parkinson’s&Disease&Centre&Discovery&Cohort&
OVERALL:&& & & & & &Euroqol & &Schwab& & &Hoehn&and&Yahr&& & & & & &LEDD& & & &UPDRS&II& & &UPDRS&IV&
Autonomic&Motor&&Neuropsychiatric&
Tremor&Freezing&&Rigidity&Gait&
BFI&–&personality&QUIP&–&compulsion&
UPDRS&I&Postural&drop&
Perdue&pegboard&Getgo&
Flamingo&UPDRS&III&–&can&be&broken&down&to&
par$cular&areas&of&the&body&&
Depression& Anxiety& Cogni$ve&func$on&
Leeds&depression&
Becks&depression&
(BDI)&
Leeds&anxiety&
MOCA&MMSE&
Phenomic&fluency&Seman$c&fluency&
Smell& Cons$pa$on& Sleep&
Sniffin& Cons$p_cat& ESS&RBD&
Dahl,&A.,&et&al.,&A"mul&ple)phenotype"imputa&on"method"for"gene&c"studies.&Nature&Gene$cs,&2016.&48(4):&p.&466b+&&
Phen
otype+A+
Phenotype+B+Ph
enotype+A+
Phenotype+B+
Iden$fying&the&underlying&phenotypic&axes,&incorpora$ng&gene$c&similarity&using&PHENIX.&
b0.6&b0.4&b0.2&
0&0.2&0.4&0.6&0.8&
Disease&du
ra$o
n&BM
I&ESS&total&
RBD&total&
Cons$p
a$on
&Leed
s&anxiety&to
tal&
Leed
s&dep
ression&
BDI&total&
QUIP&all&
MOCA
total&
Educa$
on&years&
MMSEtotal&
Phon
emic&flue
ncy&
Seman$c&flue
ncy&
Purdue
&total&
Purdue
&assem
bly&
Getgo&average&
Flam
ingo&$me&
Ortho
sta$
c&LEDD
&total&
CGIC&
Sniffi
n&total&
UPD
RS&I&
UPD
RS&II&
UPD
RS&III&
UPD
RS&IV
&UPD
RS&apathy&
UPD
RS&hallucina$o
ns&
UPD
RS&fa$g
ue&
UPD
RS&pain&
UPD
RS&con
s$pa$o
n&UPD
RS&rigidity&
UPD
RS&bradykine
sia&
UPD
RS&postural&
UPD
RS&trem
or&
UPD
RS&sp
eech&
UPD
RS&facene
ck&
UPD
RS&arm
s&UPD
RS&legs&
UPD
RS&laterality&
Phenotype&axis&1&r2&correla$o
n&
b0.6&b0.4&b0.2&
0&0.2&0.4&0.6&0.8&
Disease&du
ra$o
n&BM
I&ESS&total&
RBD&total&
Cons$p
a$on
&Leed
s&anxiety&to
tal&
Leed
s&dep
ression&
BDI&total&
QUIP&all&
MOCA
total&
Educa$
on&years&
MMSEtotal&
Phon
emic&flue
ncy&
Seman$c&flue
ncy&
Purdue
&total&
Purdue
&assem
bly&
Getgo&average&
Flam
ingo&$me&
Ortho
sta$
c&LEDD
&total&
CGIC&
Sniffi
n&total&
UPD
RS&I&
UPD
RS&II&
UPD
RS&III&
UPD
RS&IV
&UPD
RS&apathy&
UPD
RS&hallucina$o
ns&
UPD
RS&fa$g
ue&
UPD
RS&pain&
UPD
RS&con
s$pa$o
n&UPD
RS&rigidity&
UPD
RS&bradykine
sia&
UPD
RS&postural&
UPD
RS&trem
or&
UPD
RS&sp
eech&
UPD
RS&facene
ck&
UPD
RS&arm
s&UPD
RS&legs&
UPD
RS&laterality&
Phenotype&axis&1&
Anxiety&and&depression&
Increasing&score&
r2&correla$o
n&
b0.6&b0.4&b0.2&
0&0.2&0.4&0.6&0.8&
Disease&du
ra$o
n&BM
I&ESS&total&
RBD&total&
Cons$p
a$on
&Leed
s&anxiety&to
tal&
Leed
s&dep
ression&
BDI&total&
QUIP&all&
MOCA
total&
Educa$
on&years&
MMSEtotal&
Phon
emic&flue
ncy&
Seman$c&flue
ncy&
Purdue
&total&
Purdue
&assem
bly&
Getgo&average&
Flam
ingo&$me&
Ortho
sta$
c&LEDD
&total&
CGIC&
Sniffi
n&total&
UPD
RS&I&
UPD
RS&II&
UPD
RS&III&
UPD
RS&IV
&UPD
RS&apathy&
UPD
RS&hallucina$o
ns&
UPD
RS&fa$g
ue&
UPD
RS&pain&
UPD
RS&con
s$pa$o
n&UPD
RS&rigidity&
UPD
RS&bradykine
sia&
UPD
RS&postural&
UPD
RS&trem
or&
UPD
RS&sp
eech&
UPD
RS&facene
ck&
UPD
RS&arm
s&UPD
RS&legs&
UPD
RS&laterality&
Anxiety&and&depression&
Increasing&score&
Motor&symptoms&
Phenotype&axis&1&r2&correla$o
n&
b0.6&b0.4&b0.2&
0&0.2&0.4&0.6&0.8&
Disease&du
ra$o
n&BM
I&ESS&total&
RBD&total&
Cons$p
a$on
&Leed
s&anxiety&to
tal&
Leed
s&dep
ression&
BDI&total&
QUIP&all&
MOCA
total&
Educa$
on&years&
MMSEtotal&
Phon
emic&flue
ncy&
Seman$c&flue
ncy&
Purdue
&total&
Purdue
&assem
bly&
Getgo&average&
Flam
ingo&$me&
Ortho
sta$
c&LEDD
&total&
CGIC&
Sniffi
n&total&
UPD
RS&I&
UPD
RS&II&
UPD
RS&III&
UPD
RS&IV
&UPD
RS&apathy&
UPD
RS&hallucina$o
ns&
UPD
RS&fa$g
ue&
UPD
RS&pain&
UPD
RS&con
s$pa$o
n&UPD
RS&rigidity&
UPD
RS&bradykine
sia&
UPD
RS&postural&
UPD
RS&trem
or&
UPD
RS&sp
eech&
UPD
RS&facene
ck&
UPD
RS&arm
s&UPD
RS&legs&
UPD
RS&laterality&
Phenotype&axis&1&
Anxiety&and&depression&
Increasing&score&
Cogni$ve&impairment&
Motor&symptoms&
r2&correla$o
n&
6&phenotypic&axes&iden$fied&
Phenotype+axis+1+Worsening&anxiety,&depression&and&nonbtremor&motor&but&minimal&cogni$ve&decline&
Phenotype+axis+2+Worsening&anxiety,&depression&and&autonomic&symptoms&but&minimal&motor&dysfunc$on&
Phenotype+axis+3+Rigidity,&bradykinesia&and&
tremor&in&limbs,&face&and&neck&
Phenotype+axis+4+Tremor&dominant,&unilateral&
symptoms&&
Phenotype+axis+5+Worsening&posture&and&speech&
but&minimal&tremor&
Phenotype+axis+6+Worsening&mobility&and&wholebbody&movement&but&minimal&
tremor&or&bradykinesia&
Logis$c®ression&along&phenotype&axes&Phenotype&axis&1& Phenotype&axis&2& Phenotype&axis&3&
Phenotype&axis&4& Phenotype&axis&5& Phenotype&axis&6&
Gene$c&variants&are&associated&with&severity&of&clinical&phenotypes&
chr8:983
6080
5&chr8:983
7814
9&chr8:983
8733
4&chr14:22
9519
16&
chr15:97
3079
20&
Leeds&anxiety& *& *& *& *&Leeds&depression& *& *& *& *&Beck's&depression& *& *&UPDRS&I&(mood)& *& *& *& *&UPDRS&II&(daily&life)& *& *& *&UPDRS&III&(motor)&UPDRS&apathy&UPDRS&fa$gue&UPDRS&pain& *& *& *&UPDRS&cons$pa$on&UPDRS&bradykinesia&UPDRS&tremor&UPDRS&arms&
0&
1&
5&
blog10(P)&
Phenotypes&associated&with&phenotype&axis&2&
*&Significant&amer&mul$ple&tes$ng&
SNPs&
Gene$c&variants&are&associated&with&severity&of&clinical&phenotypes&
chr1:402
4069
1&chr1:402
4225
6&chr1:402
4305
6&chr1:402
4350
1&chr1:402
4722
9&chr1:402
5148
2&chr1:402
5381
0&chr1:402
5381
2&chr14:72
7937
07&
UPDRS&III&(motor)& *& *& *& *& *& *& *& *& *&UPDRS&rigidity& *&UPDRS&bradykinesia& *&UPDRS&tremor& *& *& *& *& *& *& *& *&UPDRS&arms& *& *& *& *& *& *& *& *& *&UPDRS&legs& *&
0
2
4
6
8
10
−lo
g 10(p−v
alue
)
0
20
40
60
80
100
Recom
bination rate (cM/M
b)
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0.20.40.60.8
r2
MACF1
KIAA0754 BMP8A
PPIEL
PABPC4
SNORA55
HEYL
NT5C1A
HPCAL4
PPIE
BMP8B
OXCT2
TRIT1
MYCL
MFSD2A CAP1
PPT1
RLF
40 40.2 40.4 40.6Position on chr1 (Mb)
Plotted SNPs
0&
1&
5&
blog10(P)&
Phenotypes&associated&with&phenotype&axis&3& *&Significant&amer&
mul$ple&tes$ng&
SNPs&
Gene$c®ions&affect&dis$nct&paoerns&of&phenotypes&
Genetic regions Chr 3:194252539 Chr 9:9852889 Chr 8:98360805-
98387334 Chr 14:22951916 Chr 15:97307920 Chr 1:40240691-
40253812 Chr 14:72793707 Chr 9:109461301-
109489362 Chr 17:7511934 Chr 16:78331954
Trem
or&arm
s&
Manual&dexterity&
Trem
or&legs&
Rigidity&/&bradykinesia&legs&
Daily&living&
Pain&
Apathy&&&fa$gue&
Anxiety&&&depression&
Posture&
Gene$c®ions&affec$ng&phenotype&severity&do¬&overlap&with&known&PD&
risk&variants&
SNCA;&PINK1;&PARKIN;&LRRK2…&
Conclusions&
• The&con$nuum&of&phenotypes&observed&in&the&clinic&can&be&meaningfully&represented&by&phenotypic&axes&
• 59&variants&in&10&genomic®ions&were&significantly&associated&with&specific&pa$ent&phenotypes&with&a&modestlybsized&cohort&
• Gene$c®ions&affec$ng&phenotype&severity&do¬&overlap&with&known&PD&risk&variants&
Acknowledgements&• Webber&Group&• Marchini&Group&
– Jonathan&Marchini&– Andy&Dahl&
• OPDC&– Michele&Hu&– Richard&WadebMar$ns&– Sam&Eveos&– Yoav&BenbSchlomo&– Michael&Lawton&– Fahd&Baid&
Contact:&[email protected]&