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Cracking the code-ing sequence for Parkinson’s disease

Jansen, I.E.

2017

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citation for published version (APA)

Jansen, I. E. (2017). Cracking the code-ing sequence for Parkinson’s disease.

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CHAPTER 5

Biological pathways as causal

genetic risk factors

for Parkinson’s disease

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5 ABSTRACT

Various biological pathways have been linked to Parkinson’s disease (PD). The ŝĚĞŶƟĮĐĂƟŽŶ ŽĨ ĚĞƌĞŐƵůĂƚĞĚ ĐĞůůƵůĂƌ ƉƌŽĐĞƐƐĞƐ ŝƐ ĞƐƐĞŶƟĂů ƚŽ ŝŶĐƌĞĂƐĞ ŽƵƌ understanding of PD pathogenesis which enhances the development of improved ƚƌĞĂƚŵĞŶƚĨŽƌW͘tĞƚŚĞƌĞĨŽƌĞĞǆƉůŽƌĞĚƚŚĞŐĞŶĞƟĐŝŶǀŽůǀĞŵĞŶƚŽĨWͲƌĞůĂƚĞĚ ŵĞĐŚĂŶŝƐŵƐ͕ĞŝƚŚĞƌĨŽĐƵƐŝŶŐŽŶƉĂƚŚǁĂǇƐŝŵƉůŝĞĚďǇƉƌĞǀŝŽƵƐŐĞŶĞƟĐĚŝƐĐŽǀĞƌŝĞƐ Žƌ ŽŶ ĐĞůůƵůĂƌ ƉƌŽĐĞƐƐĞƐ ƚŚĂƚ ĂƌĞ ĚĞƌĞŐƵůĂƚĞĚ ŽŶ ƚŚĞ ŐĞŶĞͲĞǆƉƌĞƐƐŝŽŶ ůĞǀĞů Ăƚ ƚŚĞ ŽŶƐĞƚ ŽĨ W ƉĂƚŚŽůŽŐǇ͘ tĞůůͲĞƐƚĂďůŝƐŚĞĚ W ŐĞŶĞƐ ǁĞƌĞ ĞǆĐůƵĚĞĚ ĨƌŽŵ ƚŚĞ ƉĂƚŚǁĂǇƐƉƌŝŽƌƚŽƚŚĞŐĞŶĞƟĐĂŶĂůǇƐĞƐƚŽĂƐƐƵƌĞƚŚĞŝĚĞŶƟĮĐĂƟŽŶŽĨŶŽǀĞůŐĞŶĞƟĐ ĂƐƐŽĐŝĂƟŽŶƐŝŐŶĂůƐ͘hƐŝŶŐ^<d͕ǁĞƚĞƐƚĞĚĨŽƌĂũŽŝŶƚĞīĞĐƚŽĨĐŽĚŝŶŐǀĂƌŝĂŶƚƐĨŽƌ ĂƚŽƚĂůŽĨϭϲďŝŽůŽŐŝĐĂůƉĂƚŚǁĂǇƐďǇĂŶĂůǇǌŝŶŐϯĚŝƐƟŶĐƚǁŚŽůĞĞǆŽŵĞƐĞƋƵĞŶĐŝŶŐ ;t^Ϳ ĚĂƚĂƐĞƚƐ ;/W' с ϭ͕ϭϲϳ W ĐĂƐĞƐ ĂŶĚ ϭ͕ϲϴϱ ĐŽŶƚƌŽůƐ͖ DĞƌĐŬ с ϭ͕ϭϯϴ W cases and 434 controls, PPMI = 364 PD cases and 159 controls). The ŵŝƚŽĐŚŽŶĚƌŝĂů

ĚǇƐĨƵŶĐƟŽŶ͕ ƌĞŶŝŶͲĂŶŐŝŽƚĞŶƐŝŶŐ ƐŝŐŶĂůŝŶŐ and ĐĂǀĞŽůĂƌͲŵĞĚŝĂƚĞĚ ĞŶĚŽĐǇƚŽƐŝƐ signaling ƉĂƚŚǁĂǇƐƐŚŽǁĞĚƐŝŐŶŝĮĐĂŶƚĂƐƐŽĐŝĂƟŽŶƐƚŽWŝŶƚŚĞ/W'ĚŝƐĐŽǀĞƌǇ

ĚĂƚĂƐĞƚ͕ǁŚŝĐŚƌĞƉůŝĐĂƚĞĚŝŶƚŚĞƚǁŽĂĚĚŝƟŽŶĂůt^ĚĂƚĂƐĞƚƐ͘&ŽƌƚŚĞŵŝƚŽĐŚŽŶĚƌŝĂů

ĚǇƐĨƵŶĐƟŽŶpathway, subsequent gene-based analyses revealed that genes of the

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5 /EdZKhd/KE

'ĞŶĞƟĐƐƚƵĚŝĞƐŽŶWĂƌŬŝŶƐŽŶ͛ƐĚŝƐĞĂƐĞ;WͿŚĂǀĞŝĚĞŶƟĮĞĚŶƵŵĞƌŽƵƐŐĞŶĞƟĐĨĂĐƚŽƌƐǁŚŝĐŚ ŝŶĐƌĞĂƐĞĚƚŚĞŬŶŽǁůĞĚŐĞŽŶƵŶĚĞƌůǇŝŶŐĂīĞĐƚĞĚďŝŽůŽŐŝĐĂůŵĞĐŚĂŶŝƐŵƐ͘1_{Mitochondrial} ĚǇƐĨƵŶĐƟŽŶŚĂƐďĞĞŶŝŵƉůŝĞĚƚŽďĞĂĐĂƵƐĞŽĨWďǇƚŚĞŝĚĞŶƟĮĐĂƟŽŶŽĨŵƵƚĂƟŽŶƐŝŶ the Mendelian genes Parkin, PINK1 and DJ-1, discovered through linkage analysis of PD ĨĂŵŝůŝĞƐǁŝƚŚĂƵƚŽƐŽŵĂůƌĞĐĞƐƐŝǀĞŝŶŚĞƌŝƚĂŶĐĞƉĂƩĞƌŶƐ͘2_{Similarly, the establishment of}

SNCA and LRRK2 ďǇďŽƚŚĨĂŵŝůǇĂŶĚƉŽƉƵůĂƟŽŶďĂƐĞĚƐƚƵĚŝĞƐ,3,4_{ƐƵŐŐĞƐƚĞĚƚŚĞƐǇŶĂƉƟĐ} ƚƌĂŶƐŵŝƐƐŝŽŶƐǇƐƚĞŵ;ĞŶĚŽͲĂŶĚĞǆŽĐǇƚŽƐŝƐͿƚŽďĞĂīĞĐƚĞĚŝŶWƉĂƚŚŽŐĞŶĞƐŝƐ͘5,6_{SNCA and}

LRRK2 ŚĂǀĞĨƵƌƚŚĞƌŵŽƌĞĨƵŶĐƟŽŶƐŝŶƚŚĞůǇƐŽƐŽŵĂůͲŵĞĚŝĂƚĞĚĂƵƚŽƉŚĂŐǇŵĞĐŚĂŶŝƐŵ͕7_a ƉĂƚŚǁĂǇŐĞŶĞƟĐĂůůǇůŝŶŬĞĚƚŽWŽĨǁŚŝĐŚƚŚĞƌĞůĂƟŽŶǁĂƐƐƚƌĞŶŐƚŚĞŶĞĚďǇƚŚĞĂĚĚŝƟŽŶĂů discovery of GBA and VPS35.7,8

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5

ϯŝŶĚĞƉĞŶĚĞŶƚǁŚŽůĞĞǆŽŵĞƐĞƋƵĞŶĐŝŶŐĚĂƚĂƐĞƚƐĐŽŵƉƌŝƐŝŶŐĂƚŽƚĂůŽĨϮ͕ϲϲϵWĐĂƐĞƐ and 2,278 controls. We selected biological mechanisms that were implied by previous ŐĞŶĞƟĐĚŝƐĐŽǀĞƌŝĞƐ͘ǇĞǆĐůƵĚŝŶŐƚŚĞŬŶŽǁŶWŐĞŶĞƐ͕ǁĞĂŝŵĞĚƚŽŝĚĞŶƟĨǇŶŽǀĞůŐĞŶĞƐ that contribute to a more detailed understanding of sub processes of these pathways. A ƐĞĐŽŶĚĂƉƉƌŽĂĐŚĞŶĐŽŵƉĂƐƐĞĚƚŚĞƐĞĂƌĐŚĨŽƌŶŽǀĞůŐĞŶĞƟĐĂůůǇŝŶǀŽůǀĞĚĐĞůůƵůĂƌƉƌŽĐĞƐƐĞƐ ĨŽƌ W͕ ďǇ ƐƚƵĚǇŝŶŐ ĚŝīĞƌĞŶĐĞƐ ŝŶ ŐĞŶĞƟĐ ǀĂƌŝĂƟŽŶ ďĞƚǁĞĞŶ W ƐƵďũĞĐƚƐ ĂŶĚ ŚĞĂůƚŚǇ controls for cellular processes that have been shown to be deregulated at an early stage ŽĨWƉĂƚŚŽůŽŐǇ;ŝĚĞŶƟĮĞĚďǇŝũŬƐƚƌĂĞƚĂů͘15_{Ϳ͘dŚĞŝĚĞŶƟĮĐĂƟŽŶŽĨŶŽǀĞůŐĞŶĞƐǁŝƚŚŝŶ} ŬŶŽǁŶWƉĂƚŚǁĂǇƐŽƌƚŚĞŽďƐĞƌǀĂƟŽŶŽĨŐĞŶĞƟĐǀĂƌŝĂƟŽŶǁŝƚŚŝŶĐŽŵƉůĞƚĞŶŽǀĞůĐĞůůƵůĂƌ ƉƌŽĐĞƐƐĞƐǁŝůůďƵŝůĚĂŵŽƌĞĐŽŵƉƌĞŚĞŶƐŝǀĞƉŝĐƚƵƌĞŽĨWĞƟŽůŽŐǇ͕ƚŚĞƌĞďǇĐŽŶƚƌŝďƵƟŶŐƚŽ ƚŚĞŬŶŽǁůĞĚŐĞƌĞƋƵŝƌĞĚĨŽƌƚŚĞĚĞǀĞůŽƉŵĞŶƚŽĨĨƌƵŝƞƵůƚŚĞƌĂƉŝĞƐĨŽƌW͘

Dd,K^

Subjects dŚŝƐƐƚƵĚǇĞŶĐŽŵƉĂƐƐĞƐϯŝŶĚĞƉĞŶĚĞŶƚĐŽŚŽƌƚƐŽĨǁŚŝĐŚƚŚĞƐƵďũĞĐƚƐŚĂǀĞŐŝǀĞŶǁƌŝƩĞŶ ŝŶĨŽƌŵĞĚ ĐŽŶƐĞŶƚ ĂŶĚ ƉĂƌƟĐŝƉĂƟŽŶ ŝŶ ŐĞŶĞƟĐ ƐƚƵĚŝĞƐ ǁĂƐ ĂƉƉƌŽǀĞĚ ďǇ ƌĞůĞǀĂŶƚ ůŽĐĂů ĞƚŚŝĐĂůĐŽŵŵŝƩĞĞƐĨŽƌŵĞĚŝĐĂůƌĞƐĞĂƌĐŚ͘dŚĞĮƌƐƚĐŽŚŽƌƚĐŽŶƐŝƐƚƐŽĨϮ͕ϴϱϮƐĂŵƉůĞƐ;ƉŽƐƚ ŝŶĚŝǀŝĚƵĂůYͿ͕ŝŶĐůƵĚŝŶŐϭ͕ϭϲϳWĐĂƐĞƐƚŚĂƚŽƌŝŐŝŶĂƚĞĨƌŽŵƚŚĞ/ŶƚĞƌŶĂƟŽŶĂůWĂƌŬŝŶƐŽŶ͛Ɛ ŝƐĞĂƐĞ 'ĞŶŽŵŝĐƐ ŽŶƐŽƌƟƵŵ ;/W'Ϳ͕ ĂŶĚ ϭ͕ϲϴϱ ŶĞƵƌŽůŽŐŝĐĂůůǇ ŚĞĂůƚŚǇ ĐŽŶƚƌŽůƐ͕ ŽĨ ǁŚŝĐŚϰϴϰĂƌĞƉĂƌƚŽĨƚŚĞ/W'ĐŽŚŽƌƚĂŶĚϭ͕ϮϬϭŽĨƚŚĞZŽƩĞƌĚĂŵ^ƚƵĚǇ16_{version 1} ;Z^yϭͿ͘ tĞ ƌĞĨĞƌ ƚŽ ƚŚŝƐ ĚĂƚĂƐĞƚ ĂƐ /W'ͲZ^yϭ ĐŽŚŽƌƚ ĂŶĚ ŝƚ ŚĂƐ ƐĞƌǀĞĚ ĂƐ ƚŚĞ ŝŶŝƟĂů ĞǆƉůŽƌĂƟŽŶĚĂƚĂƐĞƚ͘dŚĞŽƚŚĞƌƚǁŽĐŽŚŽƌƚƐǁĞƌĞƵƐĞĚĂƐƌĞƉůŝĐĂƟŽŶĚĂƚĂƐĞƚƐƚŽĐŽŶĮƌŵ ŝŶŝƟĂůĚŝƐĐŽǀĞƌŝĞƐ͘dŚĞƐĞĐŽŶĚĐŽŚŽƌƚĐŽŶƐŝƐƚƐŽĨϭ͕ϭϯϴWƉĂƟĞŶƚƐŽƌŝŐŝŶĂƟŶŐĨƌŽŵDĞƌĐŬ ZĞƐĞĂƌĐŚ>ĂďŽƌĂƚŽƌŝĞƐĂŶĚϰϯϰŶĞƵƌŽůŽŐŝĐĂůůǇŚĞĂůƚŚǇĐŽŶƚƌŽůƐĂĐĐĞƐƐĞĚƚŚƌŽƵŐŚƚŚĞƉƵďůŝĐ ƌĞƉŽƐŝƚŽƌǇĚď'ĂW͘dŚĞůĂƐƚĐŽŚŽƌƚ͕ĞŶĐŽŵƉĂƐƐŝŶŐϯϲϰWĐĂƐĞƐĂŶĚϭϱϵĐŽŶƚƌŽůƐ͕ŝƐƉĂƌƚ ŽĨƚŚĞWƌŽŐƌĞƐƐŝǀĞWĂƌŬŝŶƐŽŶ͛ƐDĂƌŬĞƌ/ŶŝƟĂƟǀĞ͕ŽĨǁŚŝĐŚǁŚŽůĞĞǆŽŵĞƐĞƋƵĞŶĐŝŶŐĚĂƚĂ is publically accessible through their database (www.ppmi-info.org/data). Demographic ƐƚĂƟƐƟĐƐŽŶƚŚĞĚŝƐƟŶĐƚĐŽŚŽƌƚƐĂƌĞĚĞƐĐƌŝďĞĚŝŶdĂďůĞϭ͘

tŚŽůĞĞǆŽŵĞƐĞƋƵĞŶĐŝŶŐ

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5

dĂďůĞϭ͘ŽŚŽƌƚŝŶĨŽƌŵĂƟŽŶ

/W'ͲZ^yϭ Merck PPMI

n samples 2.852 1.572 523

% male 55,3% 53,9% 64,4%

cases: n 1.167 1.138 364

cases: age of onset 41.2 (10.9) 64.4 (9.0) 60.1 (9.7)

cases: family history 40,4% NA 25,3%

controls: n 1685 434 159

controls: age 63.8 (17.1) 62.1 (16.2) 61.6 (10.5)

Coverage 94,4% 205,4 98,0%

Capture kit Nimblegen '/ƌĞĚƵĐĞĚ EĞǆƚĞƌĂ

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5

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5

ĐŽǀĂƌŝĂƚĞƐŝŶĂůůĂŶĂůǇƐĞƐ͗ϮϬŵƵůƟͲĚŝŵĞŶƐŝŽŶĂůƐĐĂůŝŶŐĐŽŵƉŽŶĞŶƚƐ͕t^ĐŽǀĞƌĂŐĞ;ƉƌĞͲ QC missingness) and gender.

&ŽƌĞĂĐŚƉĂƚŚǁĂǇŽĨŝŶƚĞƌĞƐƚǁĞĐŽŵƉĂƌĞĚƚŚĞŶŽŵŝŶĂůp-value of the original ŐĞŶĞͲƐĞƚ ƚŽ ƚŚĞ ĂƐƐŽĐŝĂƟŽŶ ƐŝŐŶĂů ŽĨ ϭ͕ϬϬϬ ƌĂŶĚŽŵůǇ ĚƌĂǁŶ ŐĞŶĞͲƐĞƚƐ ŵĂƚĐŚĞĚ ŽŶ ƚŚĞ ŶƵŵďĞƌ ŽĨ ŐĞŶĞƐ͘ WĞƌ ŐĞŶĞ ĂƐƐŽĐŝĂƟŽŶ ƐŝŐŶŝĮĐĂŶĐĞ ůĞǀĞůƐ ǁĞƌĞ ĐĂůĐƵůĂƚĞĚ ďǇ ŝŵƉůĞŵĞŶƟŶŐ ƚŚĞ ƌĞƐĂŵƉůŝŶŐ ŵĞƚŚŽĚ ŽĨ ^<d ǁŚŝĐŚ ŝƐ ĂĐĐŽŵƉůŝƐŚĞĚ ďǇ ϭϬ͕ϬϬϬ ƉĞƌŵƵƚĂƟŽŶƐ ƐŚƵŋŝŶŐ ƚŚĞ ĂīĞĐƟŽŶ ƐƚĂƚƵƐ͘ ŵƉŝƌŝĐĂů p-values are calculated by (n1+1)/(n+1), where n1 = the number of resampling p-values smaller than the original sample p-value and n = the number of resampling. If applicable we combined the

p-ǀĂůƵĞƐŽĨƚŚĞƌĞƉůŝĐĂƟŽŶĚĂƚĂƐĞƚƐǁŝƚŚƚŚĞ&ŝƐŚĞƌ͛ƐŵĞƚŚŽĚƚŽŽďƚĂŝŶĂŵĞƚĂp-value. dĂďůĞϮ͘'ĞŶĞͲƐĞƚƐƐĞůĞĐƚĞĚĨŽƌƉŽůǇŐĞŶĞƟĐďƵƌĚĞŶĂŶĂůǇƐĞƐŝŶW͘ WĂƚŚǁĂǇƐ n genes WŐĞŶĞƐ n tested genes 'ĞŶĞƟĐůŝƚĞƌĂƚƵƌĞ Autophagy 21 ǆ 21

Caveolar-mediated endocytosis signaling 17 ǆ 17

Clathrin-mediated endocytosis signaling 47 '<͕^zE:ϭ 45

DŝƚŽĐŚŽŶĚƌŝĂůĚǇƐĨƵŶĐƟŽŶ 128 SNCA, parkin, PINK1, DJ-1, LRRK2 116

WĚŝīĞƌĞŶƟĂůŐĞŶĞͲĞǆƉƌĞƐƐŝŽŶƐƚƵĚǇ

ĐƟŶĐǇƚŽƐŬĞůĞƚŽŶƐŝŐŶĂůŝŶŐ 34 34

ŶŐŝŽƉŽĞŝƟŶƐŝŐŶĂůŝŶŐ 22 22

ǆŽŶĂůŐƵŝĚĂŶĐĞƐŝŐŶĂůŝŶŐ 77 77

Clathrin-mediated endocytosis signaling 47 '<͕^zE:ϭ 45

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5 Z^h>d^

Rare variants dŚĞ /W' t^ ĚĂƚĂƐĞƚ ŝƐ ĐƵƌƌĞŶƚůǇ ƚŚĞ ůĂƌŐĞƐƚ t^ ĚĂƚĂƐĞƚ ŽĨ ƵŶƌĞůĂƚĞĚ WĂƌŬŝŶƐŽŶ͛Ɛ ĚŝƐĞĂƐĞĐĂƐĞƐĂŶĚǁĂƐƚŚĞƌĞĨŽƌĞŝŵƉůĞŵĞŶƚĞĚĂƐƚŚĞĚŝƐĐŽǀĞƌǇĚĂƚĂƐĞƚ͘tĞĞǆƉůŽƌĞĚĨŽƌ ƉŽůǇŐĞŶŝĐŝŶŇƵĞŶĐĞƐŽĨƌĂƌĞǀĂƌŝĂŶƚƐďǇĂŐŐƌĞŐĂƟŶŐƌĂƌĞǀĂƌŝĂŶƚƐŽǀĞƌĂŐƌŽƵƉŽĨŐĞŶĞƐ ďĞůŽŶŐŝŶŐ ƚŽ Ă ƉĂƌƟĐƵůĂƌ ďŝŽůŽŐŝĐĂů ƉĂƚŚǁĂǇ͕ ĂŝŵŝŶŐ ƚŽ ŽďƚĂŝŶ ŽƉƟŵĂů ƉŽǁĞƌ ĨŽƌ ŽƵƌ study design by increasing the number of variants that are simultaneously addressed. ŽŶƐŝĚĞƌŝŶŐ ƚŚĞ ϰ ŐĞŶĞƟĐƐͲďĂƐĞĚ ĂŶĚ ϭϯ ƚƌĂŶƐĐƌŝƉƚŽŵŝĐƐͲďĂƐĞĚ ƉĂƚŚǁĂǇƐ ;dĂďůĞ ϮͿ͕ ƚŚĞ ŐĞŶĞƟĐƐͲďĂƐĞĚ ŵŝƚŽĐŚŽŶĚƌŝĂů ĚǇƐĨƵŶĐƟŽŶ ƉĂƚŚǁĂǇ ƐŚŽǁĞĚ Ă ĐŽŶƐŝƐƚĞŶƚ ƐŝŐŶŝĮĐĂŶƚ ŐĞŶĞƟĐŝŶŇƵĞŶĐĞŽĨƌĂƌĞǀĂƌŝĂŶƚƐ;ĞŵƉŝƌŝĐĂůp фϬ͘ϬϱͿŽŶWĨŽƌƚŚĞĚŝƐƟŶĐƚĐůĂƐƐŝĮĐĂƟŽŶƐ ŽĨĨƵŶĐƟŽŶĂůǀĂƌŝĂŶƚƐ;dĂďůĞϯ͖^ƵƉƉůĞŵĞŶƚĂƌǇdĂďůĞϭͿ͘dŚŝƐĮŶĚŝŶŐƐƵŐŐĞƐƚƐƚŚĂƚ͕ďĞƐŝĚĞƐ ƚŚĞ ƉƌĞǀŝŽƵƐůǇ ƉƵďůŝƐŚĞĚ W ŐĞŶĞƐ ƚŚĂƚ ǁĞƌĞ ĞǆĐůƵĚĞĚ ĨƌŽŵ ƚŚĞ ŐĞŶĞͲƐĞƚ͕ ĂĚĚŝƟŽŶĂů ŶƵĐůĞĂƌŐĞŶĞƐƚŚĂƚĂƌĞŝŶǀŽůǀĞĚŝŶŵŝƚŽĐŚŽŶĚƌŝĂůƉƌŽĐĞƐƐĞƐŚĂƌďŽƌƌĂƌĞŐĞŶĞƟĐǀĂƌŝĂŶƚƐ ƚŚĂƚ ĂīĞĐƚ W ƉĂƚŚŽŐĞŶĞƐŝƐ͘ EŽŶĞ ŽĨ ƚŚĞ ƚƌĂŶƐĐƌŝƉƚŽŵŝĐƐͲďĂƐĞĚ ƉĂƚŚǁĂǇƐ ƐŚŽǁĞĚ ĂŶ ĂŐŐƌĞŐĂƚĞĚĞīĞĐƚŽĨƌĂƌĞǀĂƌŝĂŶƚƐŽŶW͘ dŽ ĨƵƌƚŚĞƌ ĞǆƉůŽƌĞ ƚŚĞ ŐĞŶĞƟĐ ĂƐƐŽĐŝĂƟŽŶ ŽĨ ƚŚĞ ŵŝƚŽĐŚŽŶĚƌŝĂů ĚǇƐĨƵŶĐƟŽŶ ƉĂƚŚǁĂǇ͕ǁĞĂĐĐĞƐƐĞĚƚŚĞƚǁŽĂĚĚŝƟŽŶĂůŝŶĚĞƉĞŶĚĞŶƚt^ĚĂƚĂƐĞƚƐŽĨDĞƌĐŬĂŶĚWWD/͘ dŚĞƌĂƌĞǀĂƌŝĂŶƚĂƐƐŽĐŝĂƟŽŶƐŝŐŶĂůǁĂƐƌĞƉůŝĐĂƚĞĚǁŚĞŶĐŽŵďŝŶŝŶŐďŽƚŚĚĂƚĂƐĞƚƐĨŽƌƚŚĞ amino-acid changing variants (empirical p = 0.025) and all coding variants weighted for ƚŚĞŝƌĨƵŶĐƟŽŶĂůƐĐŽƌĞ;ĞŵƉŝƌŝĐĂůp = 0.0038), which is displayed in Table 3. Although ƚŚĞ ŽƚŚĞƌ ĨƵŶĐƟŽŶĂů ĐůĂƐƐĞƐ ƌĞĂĐŚĞĚ ŶŽŵŝŶĂů ƐŝŐŶŝĮĐĂŶĐĞ͕ ƚŚĞǇ ůĂĐŬĞĚ ƐŝŐŶŝĮĐĂŶĐĞ ĂŌĞƌ ƚŚĞ ĐŽŵƉĞƟƟǀĞ ƚĞƐƚ͘ dŚĞƌĞ ŝƐ Ă ƐƵďƐƚĂŶƟĂů ĚŝīĞƌĞŶĐĞ ŝŶ ƐĂŵƉůĞ ƐŝǌĞ ĐŽŵƉĂƌŝŶŐ ƚŚĞƚǁŽƌĞƉůŝĐĂƟŽŶĚĂƚĂƐĞƚƐǁŝƚŚƚŚĞĚŝƐĐŽǀĞƌǇĚĂƚĂƐĞƚ͕ŝŵƉůǇŝŶŐůĞƐƐƉŽǁĞƌƚŽĚĞƚĞĐƚ ĂŶĂƐƐŽĐŝĂƟŽŶŝŶƚŚĞƌĞƉůŝĐĂƟŽŶĚĂƚĂƐĞƚƐ͘/ƚŝƐƚŚĞƌĞĨŽƌĞĂŶƟĐŝƉĂƚĞĚƚŚĂƚƚŚĞĂďƐĞŶĐĞŽĨ ƐŝŐŶŝĮĐĂŶĐĞĨŽƌƚŚĞϭϬ͕ϮϬĂŶĚĚŝƐƌƵƉƟǀĞǀĂƌŝĂŶƚƐƵďƐĞƚƐŝƐĂƌĞƐƵůƚŽĨůŝŵŝƚĞĚ power for the Merck and PPMI dataset.

Common and rare variants

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ĨƵƌƚŚĞƌĞǆƉůŽƌĞƚŚĞĂŐŐƌĞŐĂƚĞĚĐŽŵŵŽŶǀĂƌŝĂŶƚĞīĞĐƚƐǁŝƚŚŝŶƚŚĞƐĞďŝŽůŽŐŝĐĂůƉƌŽĐĞƐƐĞƐ͘ The ĐĂǀĞŽůĂƌͲŵĞĚŝĂƚĞĚĞŶĚŽĐǇƚŽƐŝƐƐŝŐŶĂůŝŶŐpathway did not show a burden of solely common variants (p хϬ͘ϭϵϮͿŝŶƚŚĞDĞƌĐŬŽƌWWD/t^ĚĂƚĂƐĞƚƐ͘,ŽǁĞǀĞƌ͕ǁĞŽďƐĞƌǀĞĚ ĂĐŽŵŵŽŶǀĂƌŝĂŶƚĂƐƐŽĐŝĂƟŽŶ;ĞŵƉŝƌŝĐĂůp = 0.049) for the renin-angiotensin signaling pathway in the Merck dataset (Supplementary Table 3). The PPMI dataset lacked common CADD20 variants in the genes belonging to this biological process, presumably due to ƚŚĞ ƐŵĂůů ƐĂŵƉůĞ ƐŝǌĞ͕ ĂŶĚ ĐŽƵůĚ ƚŚĞƌĞĨŽƌĞ ŶŽƚ ďĞ ƚĞƐƚĞĚ͘ DĞƚĂͲĂŶĂůǇƐŝƐ ŽĨ ƚŚĞ /W' ĂŶĚDZ<ĚĂƚĂƐĞƚƌĞƐƵůƚƐŝŶĂƐŝŐŶŝĮĐĂŶƚĂƐƐŽĐŝĂƟŽŶ;ĐŽŵďŝŶĞĚp =0.018) of common ϮϬǀĂƌŝĂŶƚƐƚŽW͕ŝŵƉůǇŝŶŐƚŚĂƚƚŚĞĂƐƐŽĐŝĂƟŽŶĐŽƵůĚďĞŐĞŶƵŝŶĞďƵƚƚŚĞƐĂŵƉůĞƐŝǌĞ should increase allowing to detect a higher number of common CADD20 variants.

&ŽƌƚŚĞũŽŝŶƚĞīĞĐƚŽĨĐŽŵŵŽŶΘƌĂƌĞǀĂƌŝĂŶƚƐǁŝƚŚŝŶƚŚĞƉƌĞĚĞĮŶĞĚďŝŽůŽŐŝĐĂů ƉĂƚŚǁĂǇƐƚŽW͕ǁĞĂŐĂŝŶĚĞƚĞĐƚĞĚƐŝŐŶŝĮĐĂŶƚĂƐƐŽĐŝĂƟŽŶĨŽƌŵŝƚŽĐŚŽŶĚƌŝĂůĚǇƐĨƵŶĐƟŽŶ and the ĐĂǀĞŽůĂƌͲŵĞĚŝĂƚĞĚĞŶĚŽĐǇƚŽƐŝƐƐŝŐŶĂůŝŶŐ(empirical p = 0.025), ĂŶĚĂĚĚŝƟŽŶĂůůǇ for the ĚŽƉĂŵŝŶĞͲZWWϯϮĨĞĞĚďĂĐŬ ŝŶ ĐDW ƐŝŐŶĂůŝŶŐ pathway (empirical p с Ϭ͘Ϭϰϱ͖ ^ƵƉƉůĞŵĞŶƚĂƌǇdĂďůĞϰͿ͘ŽŵƉĂƌŝŶŐƚŚĞƌĞƐƵůƚƐŽĨƚŚĞĞǆĐůƵƐŝǀĞůǇƌĂƌĞ͕ĞǆĐůƵƐŝǀĞůǇĐŽŵŵŽŶ and joint subset of variants for the ŵŝƚŽĐŚŽŶĚƌŝĂůĚǇƐĨƵŶĐƟŽŶgene-set (Supplementary dĂďůĞϭ͕ϮĂŶĚϰͿƐƵŐŐĞƐƚƐƚŚĂƚƚŚĞŽďƐĞƌǀĞĚŝŶŇƵĞŶĐĞǁŝƚŚŝŶĐŽŵŵŽŶΘƌĂƌĞǀĂƌŝĂŶƚƐĨŽƌ the ŵŝƚŽĐŚŽŶĚƌŝĂůĚǇƐĨƵŶĐƟŽŶpathway is driven by the rare variants. The strongest rare ǀĂƌŝĂŶƚĂƐƐŽĐŝĂƟŽŶŝƐƉƌĞƐƵŵĂďůǇĚŝůƵƚĞĚďǇƚŚĞĐŽŵŵŽŶǀĂƌŝĂŶƚĂƐƐŽĐŝĂƟŽŶ͕ƌĞƐƵůƟŶŐŝŶ ĂůĞƐƐƐƚƌŽŶŐ͕ƚŚŽƵŐŚƐƟůůƐŝŐŶŝĮĐĂŶƚ͕ƐŝŐŶĂůĨŽƌƚŚĞũŽŝŶƚƐĞƚŽĨĐŽŵŵŽŶΘƌĂƌĞǀĂƌŝĂŶƚƐ͘ dŚĞ ƐŝŐŶŝĮĐĂŶƚ ĂƐƐŽĐŝĂƟŽŶ ĨŽƌ ƚŚĞ ĐĂǀĞŽůĂƌͲŵĞĚŝĂƚĞĚ ĞŶĚŽĐǇƚŽƐŝƐ ƐŝŐŶĂůŝŶŐ pathway ĐĂƵƐĞĚďǇƚŚĞĂŐŐƌĞŐĂƚĞĚĞīĞĐƚŽĨďŽƚŚĐŽŵŵŽŶΘƌĂƌĞǀĂƌŝĂŶƚƐŝƐƌĞƉůŝĐĂƚĞĚŝŶƚŚĞWWD/ dataset, but not in the Merck dataset (Supplementary Table 3). The ĚŽƉĂŵŝŶĞͲZWϯϮŝŶ

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/W ' DZ< WWD/ Figur e 1. The electr on tr

ansport chain as part of the mit

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ƚŚĞŐĞŶĞƐǁŝƚŚĂŶŝŶĚŝǀŝĚƵĂůŐĞŶĞĂƐƐŽĐŝĂƟŽŶĨŽƌƚŚĞWWD/ĂŶĚDĞƌĐŬĚĂƚĂƐĞƚƐĂƌĞĂůƐŽ ůŽĐĂůŝǌĞĚƚŽƚŚŝƐƌĞƐƉŝƌĂƚŽƌǇĐŚĂŝŶ͘ůƚŚŽƵŐŚŶŽĞǆĂĐƚƌĞƉůŝĐĂƟŽŶŽĨŝŶĚŝǀŝĚƵĂůŐĞŶĞƐŝƐ ŽďƐĞƌǀĞĚ͕ĞǀĞƌǇt^ĚĂƚĂƐĞƚŽďƐĞƌǀĞĚĂƌĂƌĞǀĂƌŝĂŶƚĂƐƐŽĐŝĂƟŽŶĨŽƌĂƚůĞĂƐƚŽŶĞ E,͗ƵďŝƋƵŝŶŽŶĞŽǆŝĚŽƌĞĚƵĐƚĂƐĞƐƵďƵŶŝƚ;Eh&ǆͿ͕ǁŚŝĐŚĂƌĞŝŶǀŽůǀĞĚŝŶŵŝƚŽĐŚŽŶĚƌŝĂů ĐŽŵƉůĞǆ /͘ Ɛ ƚŚĞƐĞ ŐĞŶĞƐ ŚĂǀĞ ƵŶŝƋƵĞ ƐĞƋƵĞŶĐĞƐ ĂŶĚ ĂƌĞ ŶŽ ƉĂƌĂůŽŐƐ ŽĨ ĞĂĐŚ ŽƚŚĞƌ͕ ǁĞĂƌĞĐŽŶĮĚĞŶƚƚŽĞǆĐůƵĚĞƚŚĞƉŽƐƐŝďŝůŝƚǇƚŚĂƚƚŚĞƐĞƐŝŐŶŝĮĐĂŶƚĂƐƐŽĐŝĂƟŽŶƐĂƌĞďĂƐĞĚ ŽŶƐĞƋƵĞŶĐŝŶŐĞƌƌŽƌƐĚƵĞƚŽŝŶĂĚĞƋƵĂƚĞƌĞĂĚŵĂƉƉŝŶŐ͘&ŝŐƵƌĞϭĚŝƐƉůĂǇƐĂŶĞŶŚĂŶĐĞĚ graphical overview of the electron transport chain (Total ŵŝƚŽĐŚŽŶĚƌŝĂů ĚǇƐĨƵŶĐƟŽŶ ƉĂƚŚǁĂǇĚŝƐƉůĂǇĞĚŝŶ^ƵƉƉůĞŵĞŶƚĂƌǇ&ŝŐƵƌĞϭͿ͘ůƚŚŽƵŐŚŽŶĞŐĞŶĞŝƐĐŽŶƚƌŝďƵƟŶŐƚŽƚŚĞ ĨƵŶĐƟŽŶŽĨ^ƵĐĐŝŶĂƚĞͲƋƵŝŶŽŶĞŽǆŝĚŽƌĞĚƵĐƚĂƐĞ;ŵŝƚŽĐŚŽŶĚƌŝĂůĐŽŵƉůĞǆ//Ϳ͕ŵŽƐƚĂƐƐŽĐŝĂƚĞĚ ŐĞŶĞƐĂƌĞŝŶǀŽůǀĞĚŝŶŵŝƚŽĐŚŽŶĚƌŝĂůĐŽŵƉůĞǆĞƐ/͕/sĂŶĚs͘

The renin-angiotensin signaling ƉĂƚŚǁĂǇǁĂƐŐĞŶĞƟĐĂůůǇĂƐƐŽĐŝĂƚĞĚƚŽWŝŶƚŚĞ /W'ĂŶĚDZ<ĚĂƚĂƐĞƚ͘ŽƚŚĂƐƐŽĐŝĂƟŽŶƐǁĞƌĞďĂƐĞĚŽŶŽŶůǇϮǀĂƌŝĂŶƚƐ͕ǁŚŝĐŚĂƌĞ ĚŝƐƟŶĐƚďĞƚǁĞĞŶƚŚĞƚǁŽĐŽŚŽƌƚƐ;^ƵƉƉůĞŵĞŶƚĂƌǇdĂďůĞϲͿ͘ůůϰǀĂƌŝĂŶƚƐŚĂǀĞĂŚŝŐŚĞƌ D&ŝŶĐĂƐĞƐĐŽŵƉĂƌĞĚƚŽĐŽŶƚƌŽůƐ͕ŝŵƉůǇŝŶŐĂĚĂŵĂŐŝŶŐĞīĞĐƚŽĨĂŐŐƌĞŐĂƚĞĚĐŽŵŵŽŶ ǀĂƌŝĂŶƚƐǁŝƚŚŝŶƚŚŝƐƉĂƚŚǁĂǇ͘sŝƐƵĂůŝǌŝŶŐƚŚĞůŽĐĂƟŽŶŽĨƚŚĞĂīĞĐƚĞĚŐĞŶĞƐŝŶƚŚĞƉĂƚŚǁĂǇ ĚŝĂŐƌĂŵ;^ƵƉƉůĞŵĞŶƚĂƌǇ&ŝŐƵƌĞϮͿ͕ƌĞǀĞĂůƐƚŚĞĨƵŶĐƟŽŶĂůŝŶǀŽůǀĞŵĞŶƚŽĨƉƌŽĐĞƐƐĞƐĂƚƚŚĞ ƐƚĂƌƚŽĨƚŚĞďŝŽůŽŐŝĐĂůƉĂƚŚǁĂǇ͕ŝŶĐůƵĚŝŶŐĨƵŶĐƟŽŶƐŝŶŝƟĂƟŶŐƚŚĞƉĂƚŚǁĂǇ;ACE and AGT) ĂŶĚŵĞĐŚĂŶŝƐŵƐŝŶŇƵĞŶĐŝŶŐƚŚĞƚƌĂŶƐĐƌŝƉƟŽŶƉƌŽĐĞƐƐĞƐŝŶƚŚĞŶƵĐůĞƵƐ;EKyϭand MEKK1). The ĐĂǀĞŽůĂƌͲŵĞĚŝĂƚĞĚĞŶĚŽĐǇƚŽƐŝƐƐŝŐŶĂůŝŶŐƉĂƚŚǁĂǇ͕ǁŚŝĐŚƐŚŽǁĞĚĂƐŝŐŶŝĮĐĂŶƚũŽŝŶƚ ĞīĞĐƚŽĨĐŽŵŵŽŶĂŶĚƌĂƌĞǀĂƌŝĂŶƚƐŽŶW͕ĐŽŶƐƟƚƵƚĞƐŽŶůǇŽŶĞŝŶĚŝǀŝĚƵĂůŐĞŶĞĂƐƐŽĐŝĂƟŽŶ of &zEŝŶƚŚĞ/W't^ĚĂƚĂƐĞƚ;p= 0.0006 and 0.009 for the AA-chancing and CADD10 ǀĂƌŝĂŶƚ ƐƵďƐĞƚƐ͕ ƌĞƐƉĞĐƟǀĞůǇͿ͘ /ƚ ƚŚĞƌĞĨŽƌĞ ƐĞĞŵƐ ƚŚĂƚ ƚŚĞ ǀĂƌŝĂŶƚƐ ĚŝƐƚƌŝďƵƚĞĚ ŽǀĞƌ Ăůů the genes involved in ĐĂǀĞŽůĂƌͲŵĞĚŝĂƚĞĚĞŶĚŽĐǇƚŽƚƐŝƐƐŝŐŶĂůŝŶŐ pathway (Supplementary &ŝŐƵƌĞϯͿĂƌĞĐŽůůĞĐƟǀĞůǇĐŽŶƚƌŝďƵƟŶŐƚŽWƐƵƐĐĞƉƟďŝůŝƚǇ͘

/^h^^/KE

dŽ ĚĞƚĞƌŵŝŶĞ ƚŚĞ ŐĞŶĞƟĐ ĞīĞĐƚƐ ŽĨ ďŝŽůŽŐŝĐĂů ŵĞĐŚĂŶŝƐŵƐ ŽŶ W ƉĂƚŚŽŐĞŶĞƐŝƐ͕ ǁĞ ĞǆƉůŽƌĞĚϯŝŶĚĞƉĞŶĚĞŶƚǁŚŽůĞĞǆŽŵĞƐĞƋƵĞŶĐŝŶŐĚĂƚĂƐĞƚƐďǇĞƐƚĂďůŝƐŚŝŶŐĚŝīĞƌĞŶĐĞƐŝŶ ŽǀĞƌĂůůĂŐŐƌĞŐĂƚĞĚĂůůĞůĞĨƌĞƋƵĞŶĐŝĞƐďĞƚǁĞĞŶWƉĂƟĞŶƚƐĂŶĚŚĞĂůƚŚǇĐŽŶƚƌŽůƐ͘^ŝǆƚĞĞŶ ƉĂƚŚǁĂǇƐ ǁĞƌĞ ƐĞůĞĐƚĞĚ ĨŽƌ ŝŶǀĞƐƟŐĂƟŽŶ͕ ĞŝƚŚĞƌ ďĂƐĞĚ ŽŶ ĨƵŶĐƟŽŶĂů ŝŶǀŽůǀĞŵĞŶƚ ŽĨ known PD genes1_{ŽƌŽŶĂƚƌĂŶƐĐƌŝƉƚŽŵŝĐƐƐƚƵĚǇƌĞƉŽƌƟŶŐĚĞƌĞŐƵůĂƚĞĚďŝŽůŽŐŝĐĂůƉĂƚŚǁĂǇƐ} ďĂƐĞĚŽŶŐĞŶĞĞǆƉƌĞƐƐŝŽŶůĞǀĞůƐŽďƐĞƌǀĞĚĂƚƚŚĞŽŶƐĞƚ;ƌĂĂŬƐƚĂŐĞϭŽƌϮͿŽĨɲͲƐǇŶƵĐůĞŝŶ PD pathology.15_{&ŽĐƵƐŝŶŐ ŽŶ ƚŚĞ ŐĞŶĞƟĐƐͲďĂƐĞĚ ƉĂƚŚǁĂǇƐ autophagy, caveolar- and}

ĐůĂƚŚƌŝŶͲŵĞĚŝĂƚĞĚ ĞŶĚŽĐǇƚŽƐŝƐ͕ and ŵŝƚŽĐŚŽŶĚƌŝĂů ĚǇƐĨƵŶĐƟŽŶ, we aimed to improve

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the transcriptomics-based cellular processes. By grouping the genes that are encoding for the proteins that are involved in the molecular processes of interest we generated gene-ƐĞƚƐ͕ǁŚŝĐŚǁĞƌĞƚĞƐƚĞĚĨŽƌƚŚĞŝƌĐŽŵďŝŶĞĚĂƐƐŽĐŝĂƟŽŶƚŽW͘

&ŽƌƚŚĞŐĞŶĞƟĐƐͲďĂƐĞĚƉĂƚŚǁĂǇƐ͕ƚŚĞŵŝƚŽĐŚŽŶĚƌŝĂůĚǇƐĨƵŶĐƟŽŶand

caveolar-ŵĞĚŝĂƚĞĚ ĞŶĚŽĐǇƚŽƐŝƐ ƐŝŐŶĂůŝŶŐ ƉĂƚŚǁĂǇƐ ƐŚŽǁĞĚ Ă ũŽŝŶƚ ĞīĞĐƚ ŽĨ ĐŽĚŝŶŐ ǀĂƌŝĂŶƚƐ ƚŽ

W͘ZĂƌĞǀĂƌŝĂŶƚƐƚŚĂƚǁĞƌĞǁĞŝŐŚƚĞĚĂĐĐŽƌĚŝŶŐƚŽƚŚĞŝƌĨƵŶĐƟŽŶĂůĞīĞĐƚ;ƉƌĞĚŝĐƚĞĚďǇ CADD) and located within the genes of the ŵŝƚŽĐŚŽŶĚƌŝĂůĚǇƐĨƵŶĐƟŽŶpathway, showed a ĚŝīĞƌĞŶĐĞŝŶŐƌŽƵƉĞĚĂůůĞůĞĨƌĞƋƵĞŶĐǇĐŽŵƉĂƌŝŶŐWĐĂƐĞƐǀĞƌƐƵƐĐŽŶƚƌŽůƐŝŶƚŚĞ/W' ĚŝƐĐŽǀĞƌǇ ĚĂƚĂƐĞƚ͕ ĂŶĚ ƚŚĞ Ϯ ŝŶĚĞƉĞŶĚĞŶƚ ƌĞƉůŝĐĂƟŽŶ ĚĂƚĂƐĞƚƐ͕ ƚŚĞƌĞĨŽƌĞ ŐĞŶĞƌĂƟŶŐ Ă strong convincing evidence. As known PD genes (parkin, PINK1, DJ-1, LRRK2 and SNCA) ǁĞƌĞĞǆĐůƵĚĞĚĨƌŽŵƚŚĞƚĞƐƚĞĚŐĞŶĞͲƐĞƚ͕ŝƚƐƵŐŐĞƐƚƐƚŚĂƚĂĚĚŝƟŽŶĂůŐĞŶĞƐŝŵƉůŝĐĂƚĞĚŝŶ ŵŝƚŽĐŚŽŶĚƌŝĂůŚĞĂůƚŚĂƌĞĚĞƌĞŐƵůĂƚĞĚŝŶWĞƟŽůŽŐǇ͘dŽŽƵƌŬŶŽǁůĞĚŐĞ͕ƚŚŝƐƐƚƵĚǇŝƐƚŚĞ ĮƌƐƚĐŽŵƉƌĞŚĞŶƐŝǀĞĞīŽƌƚƚŽŝŶǀĞƐƟŐĂƚĞƚŚĞĐŽŶƚƌŝďƵƟŽŶŽĨǀĂƌŝĂŶƚƐŝŶŶƵĐůĞĂƌŐĞŶĞƐǁŝƚŚ ŵŝƚŽĐŚŽŶĚƌŝĂůĨƵŶĐƟŽŶƐƚŽWĞƟŽůŽŐǇ͘ůƚŚŽƵŐŚƚŚĞŵŝƚŽĐŚŽŶĚƌŝĂůŵĂŝŶƚĞŶĂŶĐĞƐǇƐƚĞŵ is comprised of 1,000 to 1,500 genes,25_{so far only 9 nuclear genes have been studied for} ƚŚĞŝƌŐĞŶĞƟĐŝŶǀŽůǀĞŵĞŶƚŝŶW͘26_{^ŵĂůůͲƐĐĂůĞĂƐƐŽĐŝĂƟŽŶƐƚƵĚŝĞƐŽĨƚŚĞƐĞŐĞŶĞƐƐƵŐŐĞƐƚ} ŝŶǀŽůǀĞŵĞŶƚŝŶŵŝƚŽĐŚŽŶĚƌŝĂůďŝŽŐĞŶĞƐŝƐĨƵŶĐƟŽŶƐ͕ŚŽǁĞǀĞƌŶŽ't^ůŽĐŝŚĂǀĞǇĞƚďĞĞŶ ůŝŶŬĞĚƚŽŵŝƚŽĐŚŽŶĚƌŝĂůĚĞƌĞŐƵůĂƟŽŶ͕ƉŽƚĞŶƟĂůůǇĚƵĞƚŽƚŚĞůŝŵŝƚĂƟŽŶŽĨ't^ƐƚƵĚŝĞƐ ƚŽĞǆĐůƵƐŝǀĞůǇƐƚƵĚǇĐŽŵŵŽŶǀĂƌŝĂŶƚƐ͘/ŶĐŽŶƚƌĂƐƚ͕ŽƵƌƐĞƋƵĞŶĐŝŶŐƐƚƵĚǇƐǇƐƚĞŵĂƟĐĂůůǇ ŝŶǀĞƐƟŐĂƚĞƐ ƚŚĞ ĂƐƐŽĐŝĂƟŽŶ ŽĨ ƌĂƌĞ ǀĂƌŝĂŶƚƐ ĞŶĂďůŝŶŐ ƚŚĞ ŝĚĞŶƟĮĐĂƟŽŶ ŽĨ ĂƐƐŽĐŝĂƟŽŶƐ ƚŚĂƚǁĞƌĞƉƌĞǀŝŽƵƐůǇŝŶĂĐĐĞƐƐŝďůĞ͘dŚĞĮŶĚŝŶŐƐŽĨŽƵƌƉŽƉƵůĂƟŽŶͲďĂƐĞĚƐƚƵĚǇŚŝŐŚůŝŐŚƚƐ ĂŐŐƌĞŐĂƚĞĚ ŐĞŶĞƟĐ ĞīĞĐƚƐ ŽĨ ŶƵĐůĞĂƌ ŵŝƚŽĐŚŽŶĚƌŝĂů ŐĞŶĞƐ͕ ŽƚŚĞƌ ƚŚĂŶ ƚŚĞ ŬŶŽǁŶ W ŐĞŶĞƐ͕ƚŚĞƌĞďǇƐƚƌĞŶŐƚŚĞŶŝŶŐƚŚĞŬŶŽǁŶƌĞůĂƟŽŶďĞƚǁĞĞŶŵŝƚŽĐŚŽŶĚƌŝĂůŚĞĂůƚŚĂŶW͘ &ƵƌƚŚĞƌŵŽƌĞ͕ŝƚĞŵƉŚĂƐŝǌĞƐƚŚĞŶĞĞĚƚŽƐŚŝŌŽƵƌƐĐŝĞŶƟĮĐĨŽĐƵƐďĞǇŽŶĚƚŚĞƉƌĞǀŝŽƵƐůǇ ŝĚĞŶƟĮĞĚŵŝƚŽĐŚŽŶĚƌŝĂůWŐĞŶĞƐ͕ƐƵĐŚĂƐDJ-1, parkin and PINK1.

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ŽĨƌĂƌĞǀĂƌŝĂŶƚƐĨŽƌƚŚĞƐƵďͲƉƌŽĐĞƐƐŽĨĐŽŵƉůĞǆ/͕ŝŵƉůǇŝŶŐǀĂƌŝĂƟŽŶŝŶŵƵůƟƉůĞĐŽŵƉůĞǆ /ŐĞŶĞƐƚŽďĞĐĂƵƐĂůĨŽƌW͘ZĞƐƉŝƌĂƚŽƌǇĐŚĂŝŶĐŽŵƉůĞǆ/ŵŝŐŚƚƚŚĞƌĞĨŽƌĞďĞĂŶĂĚĞƋƵĂƚĞ ƚĂƌŐĞƚ ƚŽ ƚƌĞĂƚ W͘ Ɛ E,ͲƋƵŝŶŽŶĞ ŽǆŝƌĞĚƵĐƚĂƐĞ ŚĂƐ ĂůƌĞĂĚǇ ďĞĞŶ ŝŵƉůŝĞĚ ƚŽ ďĞ ĚǇƐĨƵŶĐƟŽŶĂůƚŚƌŽƵŐŚĞŶǀŝƌŽŶŵĞŶƚĂůĐĂƵƐĞƐ͕ƚŚĞĂƉƉůŝĐĂƟŽŶŽĨĚƌƵŐƐƚĂƌŐĞƟŶŐĐŽŵƉůĞǆ / ĨƵŶĐƟŽŶ ŚĂƐ ďĞĞŶ ĚŝƐĐƵƐƐĞĚ͘36_{dŚĞ ĚƌƵŐ ĐŽĞŶǌǇŵĞ YϭϬ͕ ŝŶŇƵĞŶĐŝŶŐ ŵŝƚŽĐŚŽŶĚƌŝĂů} ĨƵŶĐƟŽŶ ŝŶĐůƵĚŝŶŐ ĐŽŵƉůĞǆ / ĂĐƟǀŝƚǇ͕ ŚĂƐ ĞǀĞŶ ďĞĞŶ ƚĞƐƚĞĚ ŝŶ ĐůŝŶŝĐĂů ƚƌŝĂůƐ͕ ďƵƚ ƐǇŵƉƚŽŵĂƟĐŝŵƉƌŽǀĞŵĞŶƚƐŝŶWƉĂƟĞŶƚƐŚĂǀĞŶŽƚďĞĞŶĐŽŶǀŝŶĐŝŶŐůǇƐŚŽǁŶ͘37_Besides ƚŚĞƉƵƚĂƟǀĞƐŝƚƵĂƟŽŶƚŚĂƚĐŽŵƉůĞǆ/ĂĐƟǀŝƚǇŝƐŶŽƚŐĞŶƵŝŶĞůǇĂīĞĐƚĞĚŝŶW͕ĂŶĂůƚĞƌŶĂƟǀĞ ŝŶƚĞƌƉƌĞƚĂƟŽŶ ĐŽƵůĚ ďĞ ƚŚĂƚ ǁĞ ƐƟůů ŚĂǀĞ ƉŽŽƌ ƵŶĚĞƌƐƚĂŶĚŝŶŐ ŽĨ ĞǆĂĐƚ ŝŶǀŽůǀĞŵĞŶƚ ŽĨ E,ͲƋƵŝŶŽŶĞŽǆŝƌĞĚƵĐƚĂƐĞĂŶĚŵŽƌĞĚĞƚĂŝůĞĚƐƚƵĚŝĞƐĂƌĞƌĞƋƵŝƌĞĚĨŽƌƚŚĞĚĞǀĞůŽƉŵĞŶƚ ŽĨĂĚĞƋƵĂƚĞĐŽŵƉůĞǆ/ƌĞůĂƚĞĚƚŚĞƌĂƉŝĞƐ͘&ƵƌƚŚĞƌŵŽƌĞ͕ĂƐWŝƐĂĐŽŵƉůĞǆŵƵůƟĨĂĐƚŽƌŝĂů ĚŝƐĞĂƐĞǁŝƚŚŵĂŶǇŚĞƚĞƌŽŐĞŶĞŽƵƐĨĞĂƚƵƌĞƐ͕ĂŶĂůƚĞƌŶĂƟǀĞŽƉƟŽŶĐŽƵůĚďĞƚŚĂƚƐƉĞĐŝĮĐ ƐƵďƚǇƉĞ;ƐͿĂƌĞƐĞŶƐŝƟǀĞĨŽƌĐŽŵƉůĞǆ/ƚƌĞĂƚŵĞŶƚ͘dĞƐƟŶŐŐĞŶĞƟĐƉƌĞĚŝƐƉŽƐŝƟŽŶĨŽƌE,Ͳ ƋƵŝŶŽŶĞŽǆŝƌĞĚƵĐƚĂƐĞŵĂůĨƵŶĐƟŽŶŝŶŐŵŝŐŚƚƚŚĞƌĞĨŽƌĞďĞĐƌƵĐŝĂůŝŶƐƵĐŚĐůŝŶŝĐĂůƚƌŝĂůƐ͘ dŚĞ ƐĞĐŽŶĚ ƉĂƚŚǁĂǇ ǁŝƚŚ Ă ƐŝŐŶŝĮĐĂŶƚ ĚŝīĞƌĞŶĐĞ ŝŶ ƚŚĞ ĂŐŐƌĞŐĂƚĞĚ ĞīĞĐƚ of coding variants comparing PD subjects with controls, was the ĐĂǀĞŽůĂƌͲŵĞĚŝĂƚĞĚ

ĞŶĚŽĐǇƚŽƐŝƐ signaling͘ dĞƐƟŶŐ ĨŽƌ ƚŚĞ ũŽŝŶƚ ĞīĞĐƚ ŽĨ ďŽƚŚ ƌĂƌĞ ĂŶĚ ĐŽŵŵŽŶ ǀĂƌŝĂŶƚƐ ƌĞƐƵůƚĞĚŝŶƐŝŐŶŝĮĐĂŶƚĂƐƐŽĐŝĂƟŽŶƐŝŶƚŚĞ/W'ĚŝƐĐŽǀĞƌǇĚĂƚĂƐĞƚĂŶĚƚŚĞWWD/ĚĂƚĂƐĞƚ͘ dŚĞĚĞŐƌĞĞŽĨƌĞƉůŝĐĂƟŽŶŝƐŶŽƚĂƐƐƚƌŽŶŐĂƐĨŽƌƚŚĞŵŝƚŽĐŚŽŶĚƌŝĂůĚǇƐĨƵŶĐƟŽŶpathways ďĞĐĂƵƐĞ ĂŶ ĂƐƐŽĐŝĂƟŽŶ ǁĂƐ ůĂĐŬŝŶŐ ĨŽƌ ƚŚĞ DĞƌĐŬ ĚĂƚĂƐĞƚ͘ dŚĞ ĞǆŽŵĞƐ ŽĨ ƚŚĞ DĞƌĐŬ ĚĂƚĂƐĞƚŚĂƐďĞĞŶƚĂƌŐĞƚĞĚďǇĂůŝďƌĂƌǇŝŶĐůƵĚŝŶŐĂƌĞůĂƟǀĞůǇůŽǁŶƵŵďĞƌŽĨĞǆŽŶŝĐƌĞŐŝŽŶƐ͕ ǁŚŝĐŚ ŝƐ ƉŽƚĞŶƟĂůůǇ ĐĂƵƐŝŶŐ ůŝŵŝƚĞĚ ĐŽǀĞƌĂŐĞ ĨŽƌ ƚŚĞ ŐĞŶĞƐ ŝŶ ƚŚĞ ĐĂǀĞŽůĂƌͲŵĞĚŝĂƚĞĚ ĞŶĚŽĐǇƚŽƐŝƐƐŝŐŶĂůŝŶŐƉĂƚŚǁĂǇ͕ƉƵƚĂƟǀĞůǇƌĞƐƵůƟŶŐŝŶĚĞĐƌĞĂƐĞĚƉŽǁĞƌĨŽƌƚŚŝƐƐƉĞĐŝĮĐ ŐĞŶĞͲƐĞƚ͘ůƚŚŽƵŐŚƚŚĞƌĞƉůŝĐĂƟŽŶŝŶƚŚĞWWD/ĚĂƚĂƐĞƚƐƵŐŐĞƐƚƐĂƐƵďƐƚĂŶƟĂůƉƌŽďĂďŝůŝƚǇ ŽĨĂƚƌƵĞĂƐƐŽĐŝĂƟŽŶƚŽW͕ĂŶĂůƚĞƌŶĂƟǀĞŝŶƚĞƌƉƌĞƚĂƟŽŶŝŶƐƉŝƌĞĚďǇƚŚĞŝŶǀĂůŝĚĂƟŽŶďǇ ƚŚĞ DĞƌĐŬ ĚĂƚĂƐĞƚ ĞŶĐŽŵƉĂƐƐĞƐ ƚŚĞ ĂďƐĞŶĐĞ ŽĨ Ă ŐĞŶƵŝŶĞ ŐĞŶĞƟĐ ĂƐƐŽĐŝĂƟŽŶ ĨŽƌ ƚŚŝƐ ĞŶĚŽĐǇƚŽƐŝƐŵĞĐŚĂŶŝƐŵ͘dŚĞůĂƩĞƌŝŶƚĞƌƉƌĞƚĂƟŽŶŝƐƌĞŝŶĨŽƌĐĞĚďǇƚŚĞƐƚƵĚǇŽĨŝũŬƐƚƌĂ et al.15_{͕ƌĞƉŽƌƟŶŐĂĚĞƌĞŐƵůĂƟŽŶŽĨƚŚĞĐůĂƚŚƌŝŶͲŵĞĚŝĂƚĞĚĞŶĚŽĐǇƚŽƐŝƐƐŝŐŶĂůŝŶŐƉĂƚŚǁĂǇ͕} ƌĂƚŚĞƌƚŚĂŶƚŚĞŵĞĚŝĂƟŽŶƚŚƌŽƵŐŚĐĂǀĞŽůŝŶ͘tĞĚŝĚŶŽƚŽďƐĞƌǀĞĂŶĂƐƐŽĐŝĂƟŽŶĨŽƌƚŚĞ ĐůĂƚŚƌŝŶ ŵĞĚŝĂƚĞĚ ƉĂƚŚǁĂǇ ĨŽƌ W ŽŶ ƚŚĞ ŐĞŶĞƟĐ ǀĂƌŝĂŶƚ ůĞǀĞů͘ ,ŽǁĞǀĞƌ͕ ĂĚĚŝƟŽŶĂů literature on caveolin-1 (encoded by CAV1ͿƐŚŽǁƐĂƌĞůĂƟŽŶƚŽW͕ƚŚĞƌĞďǇŝŶĨĂǀŽƌŽĨ Ă ŐĞŶƵŝŶĞ ĂƐƐŽĐŝĂƟŽŶ ŽĨ ƚŚĞ ĐĂǀĞŽůĂƌͲŵĞĚŝĂƚĞĚ ĞŶĚŽĐǇƚŽƐŝƐ ƐŝŐŶĂůŝŶŐ pathway to PD pathogenesis. Caveolin-1 is the main component of the caveolae plasma membrane and has been shown to be a substrate of parkin, ƚŚĞWŐĞŶĞŵĂŝŶůǇĨƵŶĐƟŽŶĂůŝŶŵŝƚŽĐŚŽŶĚƌŝĂů ŚĞĂůƚŚ͕ĂŶĚƐƵŐŐĞƐƚĞĚĂƐĂƉŽƚĞŶƟĂůƚŚĞƌĂƉĞƵƟĐƚĂƌŐĞƚ͘38,39_{Caveolin-1 is encoded by one}

ŽĨƚŚĞϭϳŐĞŶĞƐƚŚĂƚĞŶĐŽŵƉĂƐƐĞĚƚŚĞƚĞƐƚĞĚŐĞŶĞͲƐĞƚ͘KŶůǇŽŶĞŐĞŶĞǁŝƚŚŝŶƚŚĞcaveolar-ŵĞĚŝĂƚĞĚĞŶĚŽĐǇƚŽƐŝƐƐŝŐŶĂůŝŶŐƉĂƚŚǁĂǇƌĞĂĐŚĞĚƐŝŐŶŝĮĐĂŶƚŝŶĚŝǀŝĚƵĂůĂƐƐŽĐŝĂƟŽŶƚŽW͕

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ƚŚĂƚ ǁĞƌĞ ƌĞƉŽƌƚĞĚ ƚŽ ďĞ ƐƉĞĐŝĮĐ ĨŽƌ W ƉĂƟĞŶƚƐ͘41_{,ŽǁĞǀĞƌ͕ ĂĚĚŝƟŽŶĂů ůĂƌŐĞͲƐĐĂůĞ} ƌĞƐĞƋƵĞŶĐŝŶŐƐƚƵĚŝĞƐĂŶĚĨƵŶĐƟŽŶĂůĞǆƉĞƌŝŵĞŶƚƐĨŽĐƵƐŝŶŐŽŶƚŚĞŐĞŶĞƐŝŶǀŽůǀĞĚŝŶƚŚĞ

ĐĂǀĞŽůĂƌͲŵĞĚŝĂƚĞĚĞŶĚŽĐǇƚŽƐŝƐpathway are required to convincingly relate this cellular

ƉƌŽĐĞƐƐƚŽWĞƟŽůŽŐǇ͘

&Žƌ ƚŚĞ ƚƌĂŶƐĐƌŝƉƚŽŵŝĐƐͲďĂƐĞĚ ƉĂƚŚǁĂǇ͕ ŽŶůǇ ƚŚĞ renin-angiotensin pathway ĞŶĐŽŵƉĂƐƐĞĚ ǀĂƌŝĂŶƚƐ ƚŚĂƚ ŝŶŇƵĞŶĐĞ W ƐƵƐĐĞƉƟďŝůŝƚǇ͘ dŚŝƐ ĂƐƐŽĐŝĂƟŽŶ ƐŝŐŶĂů ǁĂƐ ĞǆĐůƵƐŝǀĞůǇĚƌŝǀĞŶďǇĂƐŵĂůůŶƵŵďĞƌŽĨĐŽŵŵŽŶǀĂƌŝĂŶƚƐŝŶƚŚĞ/W'ĂŶĚDĞƌĐŬĚĂƚĂƐĞƚ͕ ďƵƚůĂĐŬĞĚĂƌĞƉůŝĐĂƟŽŶŝŶƚŚĞWWD/ĐŽŚŽƌƚ;ϯϲϰWƐƵďũĞĐƚƐĂŶĚϭϱϵĐŽŶƚƌŽůƐͿ͘dŚĞůĂĐŬ ŽĨƐŝŐŶĂůŝŶƚŚĞWWD/ĚĂƚĂƐĞƚŝƐĂŶƟĐŝƉĂƚĞĚƚŽďĞĂƌĞƐƵůƚŽĨŝŶƐƵĸĐŝĞŶƚƉŽǁĞƌĂƐƚŚŝƐ small dataset harbored not a single common variant that was predicted to be pathogenic ĨŽƌƚŚŝƐƐƉĞĐŝĮĐƉĂƚŚǁĂǇ͘ůƚŚŽƵŐŚƚƌĂĚŝƟŽŶĂůůǇƚŚĞƌĞŶŝŶͲĂŶŐŝŽƚĞŶƐŝŶƐǇƐƚĞŵ;Z^ͿǁĂƐ ŬŶŽǁŶ ĨŽƌ ŝƚƐ ƌĞŐƵůĂƟŽŶ ŽĨ ďůŽŽĚ ƉƌĞƐƐƵƌĞ ĂŶĚ ǁĂƚĞƌͬƐĂůƚ ŚŽŵĞŽƐƚĂƐŝƐ͕ ŵŽƌĞ ƌĞĐĞŶƚůǇ ƚŚĞĞǆŝƐƚĞŶĐĞŽĨůŽĐĂůZ^ƐǇƐƚĞŵƐĂƌĞĂĐŬŶŽǁůĞĚŐĞĚ͕ŝŶĐůƵĚŝŶŐƚŚĞĐĞŶƚƌĂůZ^ĨŽƌƚŚĞ brain.42_{DŽƌĞƐƉĞĐŝĮĐĨŽƌW͕ĂŶŝŶƚƌĂĐĞůůƵůĂƌZ^ŝƐŽďƐĞƌǀĞĚĨŽƌĚŽƉĂŵŝŶĞƌŐŝĐŶĞƵƌŽŶƐ͕} ǁŚŝĐŚďĞĐŽŵĞƐŚǇƉĞƌĂĐƟǀĞŝŶƌĞƐƉŽŶƐĞƚŽĂŐĞͲƌĞůĂƚĞĚĚĞĐƌĞĂƐĞŝŶĚŽƉĂŵŝŶĞĂĐƟǀŝƚǇ͘43-47 dŚŝƐŽǀĞƌͲĂĐƟǀĂƟŽŶĞŶŚĂŶĐĞƐŶĞƵƌŽŶĂůĚĞĂƚŚ͕ŝŵƉůǇŝŶŐƚŚĞůŽĐĂůĚŽƉĂŵŝŶĞƌŐŝĐZ^ƚŽďĞ ĂƉƵƚĂƟǀĞƚĂƌŐĞƚĨŽƌWƚƌĞĂƚŵĞŶƚ͘ dŚĞĂƐƐŽĐŝĂƟŽŶƐŝŐŶĂůƐǁŝƚŚŝŶƚŚĞ/W'ĂŶĚDĞƌĐŬĚĂƚĂƐĞƚĂƌĞďŽƚŚĐŽŵƉŽƐĞĚ ŽĨ ĂŶ ĂŐŐƌĞŐĂƚĞĚ ĞīĞĐƚ ŽĨ Ϯ ĐŽŵŵŽŶ ǀĂƌŝĂŶƚƐ ƚŚĂƚ ĂƌĞ ƉƌĞĚŝĐƚĞĚ ƚŽ ďĞůŽŶŐ ƚŽ ƚŚĞ ϭй ŵŽƐƚĚĂŵĂŐŝŶŐǀĂƌŝĂŶƚƐŽĨƚŚĞŐĞŶŽŵĞ͘dŚĞϰǀĂƌŝĂŶƚƐĂƌĞƉƌĞƐĞŶƚŝŶƚŚĞϰĚŝƐƟŶĐƚŐĞŶĞƐ ͕'d͕EKyϭand MEKK1͕ǁŚŝĐŚĂůůŚĂǀĞƉƌĞǀŝŽƵƐůǇďĞĞŶĚĞƐĐƌŝďĞĚŝŶƌĞůĂƟŽŶƚŽW͘

,ŝŐŚůĞǀĞůƐŽĨƚŚĞĂŶŐŝŽƚĞŶƐŝŶͲĐŽŶǀĞƌƟŶŐĞŶǌǇŵĞ͕ĞŶĐŽĚĞĚďǇACE, are present within the nigria-striatal pathway and basal ganglia.48,49_{These protein levels are reported to be} ĚĞĐƌĞĂƐĞĚŝŶƚŚĞĐĞƌĞďƌŽƐƉŝŶĂůŇƵŝĚŽĨWƉĂƟĞŶƚƐ͘50_{&ƵƌƚŚĞƌŵŽƌĞ͕ĂĚŵŝŶŝƐƚƌĂƟŽŶŽĨĂŶ} ͲŝŶŚŝďŝƚŽƌŝŶŵƵůƟƉůĞƌŽĚĞŶƚŵŽĚĞůƐƐĞĞŵƚŽƉƌŽƚĞĐƚĂŐĂŝŶƐƚĂůŽƐƐŽĨĚŽƉĂŵŝŶĞƌŐŝĐ neurons.51-54_{Similarly in humans, a small clinical trial showed an improvement in motor} ƐǇŵƉƚŽŵƐ ĨŽƌ W ƉĂƟĞŶƚƐ ƚŚĂƚ ƌĞĐĞŝǀĞĚ ƚŚĞ ͲŝŶŚŝďŝƚŽƌ ƉĞƌŝŶĚŽƉƌŝů͘55_{These studies} ƚĂƌŐĞƟŶŐ ĂŶĚ ŝŶǀĞƐƟŐĂƟŶŐ ŽŶ ƉƌŽƚĞŝŶ ůĞǀĞůƐ ĂƌĞ ŝŵƉůŝĐĂƟŶŐ Ă ƌŽůĞ ŽĨ ͲƌĞůĂƚĞĚ ŵĞĐŚĂŶŝƐŵƐ ŝŶ W ƉĂƚŚŽŐĞŶĞƐŝƐ͘ ,ŽǁĞǀĞƌ͕ ƚŚĞ ŝŶŇƵĞŶĐĞ ŽĨ ŐĞŶĞƟĐ ǀĂƌŝĂŶƚƐ ŽŶ W ƐƵƐĐĞƉƟďŝůŝƚǇƌĞŵĂŝŶƐŝŶĐŽŶĐůƵƐŝǀĞ͕ĞǀĞŶƚŚŽƵŐŚŵƵůƟƉůĞƐƚƵĚŝĞƐŚĂǀĞďĞĞŶƉĞƌĨŽƌŵĞĚ͘ 'ĞŶĞƟĐƌĞƐĞĂƌĐŚŚĂƐĨŽĐƵƐĞĚŽŶĂϮϴϳͲďƉĚĞůĞƟŽŶƚŚĂƚǁĂƐƐƵŐŐĞƐƚĞĚƚŽďĞĞŶƌŝĐŚĞĚŝŶ

PD.56,57_{Yet recent meta-analyses contradict these results as they are unable to detect a}

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EKyϭ and MEKK1 ĂƌĞ ƌĞůĂƚĞĚ ƚŽ W ƚŚƌŽƵŐŚ ŽǆŝĚĂƟǀĞ ƐƚƌĞƐƐ ƐŝŐŶĂůŝŶŐ͘ dŚĞ ĐĞŶƚƌĂůŶĞƌǀŽƵƐƐǇƐƚĞŵƌĞƋƵŝƌĞƐĐŽŶƚƌŽůůĞĚƉƌŽĚƵĐƟŽŶŽĨƌĞĂĐƟǀĞŽǆǇŐĞŶƐƉĞĐŝĞƐ;ZK^Ϳ͕ a byproduct of mitochondrial metabolism.60_{KǀĞƌƉƌŽĚƵĐƟŽŶ ŽĨ ZK^ ĐĂƵƐĞƐ ŽǆŝĚĂƟǀĞ} ƐƚƌĞƐƐ ƚŚĂƚ ƉŽƚĞŶƟĂůůǇ ƌĞƐƵůƚƐ ŝŶ ŶĞƵƌŽĚĞŐĞŶĞƌĂƟŽŶ͘61,62_{^ƉĞĐŝĮĐ ĨŽƌ W͕ ŵŝƚŽĐŚŽŶĚƌŝĂů} ĚǇƐĨƵŶĐƟŽŶ ŝƐ ƐƵŐŐĞƐƚĞĚ ƚŽ ŐĞŶĞƌĂƚĞ ŽǆŝĚĂƟǀĞ ƐƚƌĞƐƐ͕ ǁŚŝĐŚ ǁĂƐ ĞŵƉŚĂƐŝǌĞĚ ďǇ ƚŚĞ discovery of DJ-1, parkin and PINK1.1_{/ŶƌĞůĂƟŽŶƚŽƚŚĞĮŶĚŝŶŐƐŝŶƚŚŝƐƐƚƵĚǇ͕MEKK1 is} a direct target of DJ-1 ĂŶĚĐŽŶƚƌŝďƵƚĞƐƚŽŽǆŝĚĂƟǀĞͲƐƚƌĞƐƐŝŶĚƵĐĞĚĐĞůůĚĞĂƚŚ͘63_Besides ĚǇƐĨƵŶĐƟŽŶĂůŵŝƚŽĐŚŽŶĚƌŝĂ͕64_{ĂŶĂůƚĞƌŶĂƟǀĞŵĞĐŚĂŶŝƐŵŚĂƐďĞĞŶƉƌŽƉŽƐĞĚƚŽďĞĂĐĂƵƐĞ} ĨŽƌ ŽǆŝĚĂƟǀĞ ƐƚƌĞƐƐ ŝŶ ŶĞƵƌŽĚĞŐĞŶĞƌĂƟŽŶ͕ ǁŚŝĐŚ ŝŶǀŽůǀĞƐ ƚŚĞ ŵĞŵďƌĂŶĞ ƚƌĂŶƐƉŽƌƚĞƌ EW,ŽǆŝĚĂƐĞĞŶǌǇŵĞƐƵďƵŶŝƚ͕ĞŶĐŽĚĞĚďǇϲŐĞŶĞƐŝŶĐůƵĚŝŶŐEKyϭ.65_{EKyϭŝƐĞǆƉƌĞƐƐĞĚ} ŝŶ ĚŽƉĂŵŝŶĞƌŐŝĐ ŶĞƵƌŽŶƐ ĂŶĚ ƐƚƌĞƐƐͲŝŶĚƵĐĞĚ ĂĐƟǀĂƟŽŶ ŽĨ EW, ŽǆŝĚĂƐĞ ϭ ƌĞƐƵůƚƐ ŝŶ ŽǆŝĚĂƟǀĞƐƚƌĞƐƐĂŶĚŶĞƵƌŽĚĞŐĞŶĞƌĂƟŽŶ͕66_{ƉŽƚĞŶƟĂůůǇƚŚƌŽƵŐŚŵŽĚƵůĂƟŽŶŽĨɲͲƐǇŶƵĐůĞŝŶ}

ĞǆƉƌĞƐƐŝŽŶ͘67_{In summary, literature on the renin-angiotensin mechanism and our}

ŝĚĞŶƟĮĞĚŐĞŶĞƐŝŵƉůŝĐĂƚĞĂĐŽŶƚƌŝďƵƟŽŶƚŽWƉĂƚŚŽŐĞŶĞƐŝƐ͕ůŝŬĞůǇƚŚƌŽƵŐŚĂŶŝŶƚĞƌĂĐƟŽŶ ǁŝƚŚŽǆŝĚĂƟǀĞƐƚƌĞƐƐ͘KĨŶŽƚĞ͕ƚŚŝƐƐƚƵĚǇƐƵŐŐĞƐƚƐĚĞƌĞŐƵůĂƟŽŶŽĨƚŚĞZ^ĂƐĂƉƌŝŵĂƌǇ ƉĂƚŚŽŐĞŶŝĐƐŽƵƌĐĞƌĂƚŚĞƌƚŚĂŶĂƐŝĚĞĞīĞĐƚŽĨWŶĞƵƌŽƉĂƚŚŽůŽŐǇ͘ĚĚŝƟŽŶĂůĨƵŶĐƟŽŶĂů ĞǆƉĞƌŝŵĞŶƚƐŽŶƚŚĞŝŶƚĞƌĂĐƟŽŶŽĨƌĞŶŝŶͲĂŶŐŝŽƚĞŶƐŝŶĂŶĚŽǆŝĚĂƟǀĞƐƚƌĞƐƐƉƌŽĐĞƐƐĞƐƐŚŽƵůĚ ĞůƵĐŝĚĂƚĞƚŚĞŐĞŶĞƌĂůƉĂƚŚŽŐĞŶŝĐŵĞĐŚĂŶŝƐŵĐŽŶƚƌŝďƵƟŶŐƚŽWƐƵƐĐĞƉƟďŝůŝƚǇ͘

Besides the renin-angiotensin signaling pathway, no other transcriptomics-based ƉĂƚŚǁĂǇ ŚĂƌďŽƌĞĚ ǀĂƌŝĂŶƚƐ ǁŝƚŚ ĂŶ ĂŐŐƌĞŐĂƚĞĚ ĞīĞĐƚ ŽŶ W͘ ůƚŚŽƵŐŚ ŶŽ ƐŝŐŶŝĮĐĂŶƚ ĂƐƐŽĐŝĂƟŽŶƐǁĞƌĞĚĞƚĞĐƚĞĚ͕ŝƚŝƐŝŵƉŽƐƐŝďůĞƚŽĚƌĂǁĚĞĮŶŝƟǀĞĐŽŶĐůƵƐŝŽŶƐŽŶƚŚĞŐĞŶĞƟĐ ĐŽŶƚƌŝďƵƟŽŶ ŽĨ ƚŚĞƐĞ ƉĂƚŚǁĂǇƐ ƚŽ W ƐƵƐĐĞƉƟďŝůŝƚǇ͘ dŚƌĞĞ ƐĐĞŶĂƌŝŽƐ ŵŝŐŚƚ ďĞ ĐĂƵƐŝŶŐ ƚŚĞĂďƐĞŶĐĞŽĨĂŶĂƐƐŽĐŝĂƟŽŶ͘KŶĞŽƉƟŽŶǁŽƵůĚďĞƚŚĂƚƚŚĞĚĞƌĞŐƵůĂƟŽŶŽďƐĞƌǀĞĚŽŶ ŐĞŶĞͲĞǆƉƌĞƐƐŝŽŶůĞǀĞůŝƐŐĞŶƵŝŶĞ͕ďƵƚƚŚŝƐŝƐŶŽƚĐĂƵƐĞĚďǇŐĞŶĞƟĐĚĞĨĞĐƚƐ͘ůƚĞƌŶĂƟǀĞůǇ͕ although Dijkstra et al.1_{ŚĂǀĞƉĞƌĨŽƌŵĞĚĐĂƌĞĨƵůĞǆƉĞƌŝŵĞŶƚƐĂŶĚĂŶĂůǇƐĞƐ͕ƚŚĞŝƌŝŵƉůŝĞĚ} ƉĂƚŚǁĂǇƐŵŝŐŚƚďĞĨĂůƐĞƉŽƐŝƟǀĞƐ͘dŚĞĚĂƚĂƐĞƚĐŽŶƐŝƐƚĞĚŽĨƉŽƐƚͲŵŽƌƚĞŵƐƵďƐƚĂŶƟĂŶŝŐƌĂ ďƌĂŝŶƟƐƐƵĞŽĨŽŶůǇϱŝŶĚŝǀŝĚƵĂůƐǁŝƚŚĞĂƌůǇͲƐƚĂŐĞɲͲƐǇŶƵĐůĞŝŶƉĂƚŚŽůŽŐǇ;ƌĂĂŬƐƚĂŐĞϭĂŶĚ 2) and 8 controls (Braak stage 0).15_{This small number of samples may have caused spurious} outcomes and, perhaps of even more impact, have missed truly associated pathways due ƚŽŝŶƐƵĸĐŝĞŶƚƉŽǁĞƌ͘ůĂƐƚŽƉƟŽŶǁŽƵůĚďĞƚŚĂƚƚŚĞĚĞĮŶĞĚƉĂƚŚǁĂǇƐĂƌĞŐĞŶƵŝŶĞůǇ associated to PD on both transcriptomics and genomics level, but the tested WES datasets ĂƌĞŽĨŝŶƐƵĸĐŝĞŶƚƐŝǌĞƚŽƌĞĂĐŚĂĚĞƋƵĂƚĞƉŽǁĞƌƚŽĚĞƚĞĐƚƚŚĞƐĞŐĞŶĞƟĐĂƐƐŽĐŝĂƟŽŶƐ͘ ƉŽƐŝƟǀĞƐŝĚĞͲĞīĞĐƚŽĨŐĞŶĞͲƐĞƚĂƐƐŽĐŝĂƟŽŶĂŶĂůǇƐŝƐƌĂƚŚĞƌƚŚĂŶŐĞŶĞͲďĂƐĞĚĂŶĂůǇƐŝƐ͕ŝƐ ƚŚĞŝŶĐƌĞĂƐĞŝŶƐƚĂƟƐƟĐĂůƉŽǁĞƌƚŽĚĞƚĞĐƚĂŶĂƐƐŽĐŝĂƟŽŶƐŝŐŶĂů͕ƐƉĞĐŝĮĐĂůůǇŝŶƚŚĞĐĂƐĞŽĨ smaller datasets.15_{KŶĞŝŵƉŽƌƚĂŶƚĐŽŶĚŝƟŽŶƚŚĂƚŚĂƐƚŽďĞŵĞƚŝƐƚŚĂƚĂůĂƌŐĞƉĂƌƚŽĨƚŚĞ} included genes are genuinely involved in PD pathogenesis as non-associated genes will ĚŝůƵƚĞƚŚĞŽǀĞƌĂůůĂƐƐŽĐŝĂƟŽŶƐŝŐŶĂů͘

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ϭ͘ dƌŝŶŚ:͕&ĂƌƌĞƌD͘ĚǀĂŶĐĞƐŝŶƚŚĞŐĞŶĞƟĐƐ of Parkinson disease. Nature reviews NeurologyϮϬϭϯ͖ϵ;ϴͿ͗ϰϰϱͲϱϰ͘

Ϯ͘ ŽŶŝĨĂƟ s͘ ƵƚŽƐŽŵĂů ƌĞĐĞƐƐŝǀĞ parkinsonism. WĂƌŬŝŶƐŽŶŝƐŵ Θ ƌĞůĂƚĞĚ ĚŝƐŽƌĚĞƌƐϮϬϭϮ͖ϭϴ^ƵƉƉůϭ͗^ϰͲϲ͘

ϯ͘ ŽŶŝĨĂƟs͘'ĞŶĞƟĐƐŽĨWĂƌŬŝŶƐŽŶ͛ƐĚŝƐĞĂƐĞͲ -state of the art, 2013. Parkinsonism & ƌĞůĂƚĞĚĚŝƐŽƌĚĞƌƐϮϬϭϰ͖ϮϬ^ƵƉƉůϭ͗^ϮϯͲϴ͘ ϰ͘ ^ŝŵŽŶͲ^ĂŶĐŚĞǌ :͕ ^ĐŚƵůƚĞ ͕ ƌĂƐ :D͕ Ğƚ Ăů͘ 'ĞŶŽŵĞͲǁŝĚĞ ĂƐƐŽĐŝĂƟŽŶ ƐƚƵĚǇ ƌĞǀĞĂůƐŐĞŶĞƟĐƌŝƐŬƵŶĚĞƌůǇŝŶŐWĂƌŬŝŶƐŽŶ͛Ɛ disease. EĂƚƵƌĞ ŐĞŶĞƟĐƐ ϮϬϬϵ͖ ϰϭ;ϭϮͿ͗ 1308-12. ϱ͘ >ĂƐŚƵĞů,͕KǀĞƌŬZ͕KƵĞƐůĂƟ͕DĂƐůŝĂŚ E. The many faces of alpha-synuclein: ĨƌŽŵƐƚƌƵĐƚƵƌĞĂŶĚƚŽǆŝĐŝƚǇƚŽƚŚĞƌĂƉĞƵƟĐ target. Nature reviews NeuroscienceϮϬϭϯ͖ 14(1): 38-48.

ϲ͘ ^ŚŝŶ E͕ :ĞŽŶŐ ,͕ <ǁŽŶ :͕ Ğƚ Ăů͘ >ZZ<Ϯ ƌĞŐƵůĂƚĞƐ ƐǇŶĂƉƟĐ ǀĞƐŝĐůĞ ĞŶĚŽĐǇƚŽƐŝƐ͘ Experimental cell researchϮϬϬϴ͖ϯϭϰ;ϭϬͿ͗ 2055-65. ϳ͘ DĂŶǌŽŶŝ ͕ >ĞǁŝƐ W͘ ǇƐĨƵŶĐƟŽŶ ŽĨ ƚŚĞ ĂƵƚŽƉŚĂŐǇͬůǇƐŽƐŽŵĂů ĚĞŐƌĂĚĂƟŽŶ ƉĂƚŚǁĂǇŝƐĂƐŚĂƌĞĚĨĞĂƚƵƌĞŽĨƚŚĞŐĞŶĞƟĐ synucleinopathies. &^ũŽƵƌŶĂů͗ŽĸĐŝĂů ƉƵďůŝĐĂƟŽŶŽĨƚŚĞ&ĞĚĞƌĂƟŽŶŽĨŵĞƌŝĐĂŶ ^ŽĐŝĞƟĞƐ ĨŽƌ ǆƉĞƌŝŵĞŶƚĂů ŝŽůŽŐǇ ϮϬϭϯ͖ 27(9): 3424-9. ϴ͘ DŝƵƌĂ͕,ĂƐĞŐĂǁĂd͕<ŽŶŶŽD͕ĞƚĂů͘sW^ϯϱ ĚǇƐĨƵŶĐƟŽŶŝŵƉĂŝƌƐůǇƐŽƐŽŵĂůĚĞŐƌĂĚĂƟŽŶ ŽĨ ĂůƉŚĂͲƐǇŶƵĐůĞŝŶ ĂŶĚ ĞǆĂĐĞƌďĂƚĞƐ ŶĞƵƌŽƚŽǆŝĐŝƚǇ ŝŶ Ă ƌŽƐŽƉŚŝůĂ ŵŽĚĞů ŽĨ Parkinson’s disease. Neurobiology of ĚŝƐĞĂƐĞϮϬϭϰ͖ϳϭ͗ϭͲϭϯ͘

ϵ͘ <ĂůŝĂ >s͕ >ĂŶŐ ͘ WĂƌŬŝŶƐŽŶ͛Ɛ ĚŝƐĞĂƐĞ͘ LancetϮϬϭϱ͖ϯϴϲ;ϵϵϵϲͿ͗ϴϵϲͲϵϭϮ͘

ϭϬ͘ ƵŬĞ ͕ DŽƌĂŶ >͕ <ĂůĂŝƚǌĂŬŝƐ D͕ Ğƚ al. Transcriptome analysis reveals link between proteasomal and mitochondrial

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ϭϭ͘ DŽŶƟ ͕ ŽŶĚŝ ,͕ hƌďĂŶŝ ͕ &ĂƐĂŶŽ D͕ Alberio T. Systems biology analysis of ƚŚĞ ƉƌŽƚĞŽŵŝĐ ĂůƚĞƌĂƟŽŶƐ ŝŶĚƵĐĞĚ ďǇ MPP(+), a Parkinson’s disease-related ŵŝƚŽĐŚŽŶĚƌŝĂů ƚŽǆŝŶ͘ &ƌŽŶƟĞƌƐ ŝŶ ĐĞůůƵůĂƌ neuroscienceϮϬϭϱ͖ϵ͗ϭϰ͘

ϭϮ͘ ^ƌŝǀĂƐƚĂǀĂ'͕^ŝŶŐŚ<͕dŝǁĂƌŝDE͕^ŝŶŐŚDW͘ Proteomics in Parkinson’s disease: current ƚƌĞŶĚƐ͕ ƚƌĂŶƐůĂƟŽŶĂů ƐŶĂŐƐ ĂŶĚ ĨƵƚƵƌĞ ƉŽƐƐŝďŝůŝƟĞƐ͘ Expert review of proteomics ϮϬϭϬ͖ϳ;ϭͿ͗ϭϮϳͲϯϵ͘

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21. Wu MC, Lee S, Cai T, Li Y, Boehnke M, Lin y͘ ZĂƌĞͲǀĂƌŝĂŶƚ ĂƐƐŽĐŝĂƟŽŶ ƚĞƐƟŶŐ ĨŽƌ sequencing data with the sequence kernel ĂƐƐŽĐŝĂƟŽŶ ƚĞƐƚ͘ ŵĞƌŝĐĂŶ ũŽƵƌŶĂů ŽĨ ŚƵŵĂŶŐĞŶĞƟĐƐϮϬϭϭ͖ϴϵ;ϭͿ͗ϴϮͲϵϯ͘ 22. Lee S, Emond MJ, Bamshad MJ, et al.

KƉƟŵĂůƵŶŝĮĞĚĂƉƉƌŽĂĐŚĨŽƌƌĂƌĞͲǀĂƌŝĂŶƚ ĂƐƐŽĐŝĂƟŽŶ ƚĞƐƟŶŐ ǁŝƚŚ ĂƉƉůŝĐĂƟŽŶ ƚŽ ƐŵĂůůͲƐĂŵƉůĞ ĐĂƐĞͲĐŽŶƚƌŽů ǁŚŽůĞͲĞǆŽŵĞ sequencing studies. ŵĞƌŝĐĂŶ ũŽƵƌŶĂů ŽĨ ŚƵŵĂŶŐĞŶĞƟĐƐϮϬϭϮ͖ϵϭ;ϮͿ͗ϮϮϰͲϯϳ͘ Ϯϯ͘ /ŽŶŝƚĂͲ>ĂǌĂ/͕>ĞĞ^͕DĂŬĂƌŽǀs͕ƵǆďĂƵŵ :͕ >ŝŶ y͘ ^ĞƋƵĞŶĐĞ ŬĞƌŶĞů ĂƐƐŽĐŝĂƟŽŶ ƚĞƐƚƐĨŽƌƚŚĞĐŽŵďŝŶĞĚĞīĞĐƚŽĨƌĂƌĞĂŶĚ common variants. ŵĞƌŝĐĂŶ ũŽƵƌŶĂů ŽĨ ŚƵŵĂŶŐĞŶĞƟĐƐϮϬϭϯ͖ϵϮ;ϲͿ͗ϴϰϭͲϱϯ͘ 24. Nunnari J, Suomalainen A. Mitochondria:

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Ϯϳ͘ WŝĐŬƌĞůůD͕zŽƵůĞZ:͘dŚĞƌŽůĞƐŽĨW/E<ϭ͕ ƉĂƌŬŝŶ͕ ĂŶĚ ŵŝƚŽĐŚŽŶĚƌŝĂů ĮĚĞůŝƚǇ ŝŶ Parkinson’s disease. Neuron ϮϬϭϱ͖ ϴϱ;ϮͿ͗ 257-73.

Ϯϴ͘ >ĞŶĂǌ '͕ &ĂƚŽ Z͕ 'ĞŶŽǀĂ D>͕ ĞƌŐĂŵŝŶŝ C, Bianchi C, Biondi A. Mitochondrial

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Ϯϵ͘ ŽǀĞ :͕ WƌŽƵ ͕ WĞƌŝĞƌ ͕ WƌǌĞĚďŽƌƐŬŝ ^͘ dŽǆŝŶͲŝŶĚƵĐĞĚ ŵŽĚĞůƐ ŽĨ WĂƌŬŝŶƐŽŶ͛Ɛ disease. EĞƵƌŽZǆ ͗ ƚŚĞ ũŽƵƌŶĂů ŽĨ ƚŚĞ American Society for Experimental EĞƵƌŽdŚĞƌĂƉĞƵƟĐƐϮϬϬϱ͖Ϯ;ϯͿ͗ϰϴϰͲϵϰ͘ ϯϬ͘ ĞƚĂƌďĞƚ Z͕ ^ŚĞƌĞƌ d͕ DĂĐ<ĞŶǌŝĞ '͕

'ĂƌĐŝĂͲKƐƵŶĂ D͕ WĂŶŽǀ s͕ 'ƌĞĞŶĂŵǇƌĞ :d͘ ŚƌŽŶŝĐ ƐǇƐƚĞŵŝĐ ƉĞƐƟĐŝĚĞ ĞǆƉŽƐƵƌĞ reproduces features of Parkinson’s disease. Nature neuroscienceϮϬϬϬ͖ϯ;ϭϮͿ͗ 1301-6.

ϯϭ͘ WĂƌŬĞƌ t͕ :ƌ͕͘ ŽǇƐŽŶ ^:͕ WĂƌŬƐ :<͘ ďŶŽƌŵĂůŝƟĞƐ ŽĨ ƚŚĞ ĞůĞĐƚƌŽŶ ƚƌĂŶƐƉŽƌƚ chain in idiopathic Parkinson’s disease. Annals of neurologyϭϵϴϵ͖Ϯϲ;ϲͿ͗ϳϭϵͲϮϯ͘ ϯϮ͘ >ĂŶŐƐƚŽŶ :t͕ &ŽƌŶŽ >^͕ dĞƚƌƵĚ :͕ ZĞĞǀĞƐ '͕<ĂƉůĂŶ:͕<ĂƌůƵŬ͘ǀŝĚĞŶĐĞŽĨĂĐƟǀĞ ŶĞƌǀĞĐĞůůĚĞŐĞŶĞƌĂƟŽŶŝŶƚŚĞƐƵďƐƚĂŶƟĂ ŶŝŐƌĂ ŽĨ ŚƵŵĂŶƐ ǇĞĂƌƐ ĂŌĞƌ ϭͲŵĞƚŚǇůͲ 4-phenyl-1,2,3,6-tetrahydropyridine ĞǆƉŽƐƵƌĞ͘ Annals of neurology ϭϵϵϵ͖ 46(4): 598-605. ϯϯ͘ &ƌĞŝƌĞ ͕ <ŽŝĨŵĂŶ ^͘ WĞƐƟĐŝĚĞ ĞǆƉŽƐƵƌĞ and Parkinson’s disease: epidemiological ĞǀŝĚĞŶĐĞ ŽĨ ĂƐƐŽĐŝĂƟŽŶ͘ Neurotoxicology ϮϬϭϮ͖ϯϯ;ϱͿ͗ϵϰϳͲϳϭ͘

ϯϰ͘ DŝŵĂŬŝD͕tĂŶŐy͕DĐ<ĞŶǌŝĞD͕dŚŽƌďƵƌŶ Z͕ZǇĂŶDd͘hŶĚĞƌƐƚĂŶĚŝŶŐŵŝƚŽĐŚŽŶĚƌŝĂů ĐŽŵƉůĞǆ/ĂƐƐĞŵďůǇŝŶŚĞĂůƚŚĂŶĚĚŝƐĞĂƐĞ͘ Biochimica et biophysica acta ϮϬϭϮ͖ 1817(6): 851-62. ϯϱ͘ ,ĂƩŽƌŝE͕zŽƐŚŝŶŽ,͕dĂŶĂŬĂD͕^ƵǌƵŬŝ,͕ DŝǌƵŶŽz͘'ĞŶŽƚǇƉĞŝŶƚŚĞϮϰͲŬĂƐƵďƵŶŝƚ ŐĞŶĞ;Eh&sϮͿŽĨŵŝƚŽĐŚŽŶĚƌŝĂůĐŽŵƉůĞǆ / ĂŶĚ ƐƵƐĐĞƉƟďŝůŝƚǇ ƚŽ WĂƌŬŝŶƐŽŶ ĚŝƐĞĂƐĞ͘ Genomicsϭϵϵϴ͖ϰϵ;ϭͿ͗ϱϮͲϴ͘

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Ăů͘ ŽĞŶǌǇŵĞ YϭϬ ĨŽƌ WĂƟĞŶƚƐ ǁŝƚŚ WĂƌŬŝŶƐŽŶ͛ƐŝƐĞĂƐĞ͗^ǇƐƚĞŵĂƟĐZĞǀŝĞǁ and Meta-Analysis. CNS & neurological ĚŝƐŽƌĚĞƌƐĚƌƵŐƚĂƌŐĞƚƐϮϬϭϲ͖ϭϱ;ϭͿ͗ϰϱͲϱϯ͘ ϯϴ͘ ŚĂ ^,͕ ŚŽŝ zZ͕ ,ĞŽ ,͕ Ğƚ Ăů͘ >ŽƐƐ ŽĨ ƉĂƌŬŝŶ ƉƌŽŵŽƚĞƐ ůŝƉŝĚ ƌĂŌƐͲĚĞƉĞŶĚĞŶƚ ĞŶĚŽĐǇƚŽƐŝƐ ƚŚƌŽƵŐŚ ĂĐĐƵŵƵůĂƟŶŐ ĐĂǀĞŽůŝŶͲϭ͗ ŝŵƉůŝĐĂƟŽŶƐ ĨŽƌ WĂƌŬŝŶƐŽŶ͛Ɛ disease. DŽůĞĐƵůĂƌ ŶĞƵƌŽĚĞŐĞŶĞƌĂƟŽŶ ϮϬϭϱ͖ϭϬ͗ϲϯ͘ ϯϵ͘ ,ĂƐŚŝŵŽƚŽ D͕ dĂŬĞŶŽƵĐŚŝ d͕ ZŽĐŬĞŶƐƚĞŝŶ E, Masliah E. Alpha-synuclein up-regulates ĞǆƉƌĞƐƐŝŽŶ ŽĨ ĐĂǀĞŽůŝŶͲϭ ĂŶĚ ĚŽǁŶͲ ƌĞŐƵůĂƚĞƐ ĞǆƚƌĂĐĞůůƵůĂƌ ƐŝŐŶĂůͲƌĞŐƵůĂƚĞĚ ŬŝŶĂƐĞĂĐƟǀŝƚǇŝŶϭϬϯŶĞƵƌŽďůĂƐƚŽŵĂĐĞůůƐ͗ role in the pathogenesis of Parkinson’s disease. Journal of neurochemistry ϮϬϬϯ͖ 85(6): 1468-79.

ϰϬ͘ tĂƌǇ <<͕ DĂƌŝŽƫ ͕ ƵƌǌŽůŽ ͕ 'ŝĂŶĐŽƫ &'͘ ƌĞƋƵŝƌĞŵĞŶƚ ĨŽƌ ĐĂǀĞŽůŝŶͲϭ ĂŶĚ ĂƐƐŽĐŝĂƚĞĚŬŝŶĂƐĞ&ǇŶŝŶŝŶƚĞŐƌŝŶƐŝŐŶĂůŝŶŐ and anchorage-dependent cell growth. Cellϭϵϵϴ͖ϵϰ;ϱͿ͗ϲϮϱͲϯϰ͘

41. Darvish H, Heidari A, Hosseinkhani S, et Ăů͘ŝĂƐĞĚŚŽŵŽǌǇŐŽƵƐŚĂƉůŽƚǇƉĞƐĂĐƌŽƐƐ the human caveolin 1 upstream purine ĐŽŵƉůĞǆŝŶWĂƌŬŝŶƐŽŶ͛ƐĚŝƐĞĂƐĞ͘Journal of ŵŽůĞĐƵůĂƌŶĞƵƌŽƐĐŝĞŶĐĞ͗DEϮϬϭϯ͖ϱϭ;ϮͿ͗ 389-93.

42. Saavedra JM. Brain angiotensin II: new ĚĞǀĞůŽƉŵĞŶƚƐ͕ƵŶĂŶƐǁĞƌĞĚƋƵĞƐƟŽŶƐĂŶĚ ƚŚĞƌĂƉĞƵƟĐ ŽƉƉŽƌƚƵŶŝƟĞƐ͘ ĞůůƵůĂƌ ĂŶĚ molecular neurobiology ϮϬϬϱ͖ Ϯϱ;ϯͲϰͿ͗ 485-512. ϰϯ͘ ZĞǇ W͕ >ŽƉĞǌͲZĞĂů ͕ ^ĂŶĐŚĞǌͲ/ŐůĞƐŝĂƐ ^͕ DƵŶŽǌ ͕ ^ŽƚŽͲKƚĞƌŽ Z͕ >ĂďĂŶĚĞŝƌĂͲ 'ĂƌĐŝĂ :>͘ ŶŐŝŽƚĞŶƐŝŶ ƚǇƉĞͲϭͲƌĞĐĞƉƚŽƌ ĂŶƚĂŐŽŶŝƐƚƐ ƌĞĚƵĐĞ ϲͲŚǇĚƌŽǆǇĚŽƉĂŵŝŶĞ ƚŽǆŝĐŝƚǇ ĨŽƌ ĚŽƉĂŵŝŶĞƌŐŝĐ ŶĞƵƌŽŶƐ͘ Neurobiology of aging ϮϬϬϳ͖ Ϯϴ;ϰͿ͗ ϱϱϱͲ 67. ϰϰ͘ ZŽĚƌŝŐƵĞǌͲWĂůůĂƌĞƐ :͕ ZĞǇ W͕ WĂƌŐĂ :͕ DƵŶŽǌ͕'ƵĞƌƌĂD:͕>ĂďĂŶĚĞŝƌĂͲ'ĂƌĐŝĂ:>͘ Brain angiotensin enhances dopaminergic ĐĞůů ĚĞĂƚŚ ǀŝĂ ŵŝĐƌŽŐůŝĂů ĂĐƟǀĂƟŽŶ ĂŶĚ EW,ͲĚĞƌŝǀĞĚ ZK^͘ Neurobiology of ĚŝƐĞĂƐĞϮϬϬϴ͖ϯϭ;ϭͿ͗ϱϴͲϳϯ͘ ϰϱ͘ :ŽŐůĂƌ ͕ ZŽĚƌŝŐƵĞǌͲWĂůůĂƌĞƐ :͕ ZŽĚƌŝŐƵĞǌͲ WĞƌĞǌ /͕ ZĞǇ W͕ 'ƵĞƌƌĂ D:͕ >ĂďĂŶĚĞŝƌĂͲ 'ĂƌĐŝĂ :>͘ dŚĞ ŝŶŇĂŵŵĂƚŽƌǇ ƌĞƐƉŽŶƐĞ ŝŶ the MPTP model of Parkinson’s disease is mediated by brain angiotensin: relevance to progression of the disease. Journal of neurochemistryϮϬϬϵ͖ϭϬϵ;ϮͿ͗ϲϱϲͲϲϵ͘ ϰϲ͘ ĂǁĂĚĂtD͕ĂŶŶŝŶŐĞƌ'W͕dŚŽƌŶƚŽŶ:͕Ğƚ

Ăů͘'ĞŶĞƌĂƟŽŶŽĨƌĞĂĐƟǀĞŽǆǇŐĞŶƐƉĞĐŝĞƐ in 1-methyl-4-phenylpyridinium (MPP+) treated dopaminergic neurons occurs as ĂŶ EW, ŽǆŝĚĂƐĞͲĚĞƉĞŶĚĞŶƚ ƚǁŽͲǁĂǀĞ cascade. :ŽƵƌŶĂů ŽĨ ŶĞƵƌŽŝŶŇĂŵŵĂƟŽŶ ϮϬϭϭ͖ϴ͗ϭϮϵ͘

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328(2): 215-21.

ϱϭ͘ :ĞŶŬŝŶƐ d͕ DĞŶĚĞůƐŽŚŶ &͕ ŚĂŝ ^z͘ ŶŐŝŽƚĞŶƐŝŶͲĐŽŶǀĞƌƟŶŐ ĞŶǌǇŵĞ modulates dopamine turnover in the striatum. Journal of neurochemistryϭϵϵϳ͖ 68(3): 1304-11.

52. Jenkins TA, Wong JY, Howells DW, DĞŶĚĞůƐŽŚŶ&͕ŚĂŝ^z͘īĞĐƚŽĨĐŚƌŽŶŝĐ ĂŶŐŝŽƚĞŶƐŝŶͲĐŽŶǀĞƌƟŶŐ ĞŶǌǇŵĞ ŝŶŚŝďŝƟŽŶ on striatal dopamine content in the MPTP-treated mouse. Journal of neurochemistry ϭϵϵϵ͖ϳϯ;ϭͿ͗ϮϭϰͲϵ͘

ϱϯ͘ >ŽƉĞǌͲZĞĂů ͕ ZĞǇ W͕ ^ŽƚŽͲKƚĞƌŽ Z͕ DĞŶĚĞǌͲůǀĂƌĞǌ ͕ >ĂďĂŶĚĞŝƌĂͲ'ĂƌĐŝĂ :>͘ ŶŐŝŽƚĞŶƐŝŶͲĐŽŶǀĞƌƟŶŐ ĞŶǌǇŵĞ ŝŶŚŝďŝƟŽŶ ƌĞĚƵĐĞƐ ŽǆŝĚĂƟǀĞ ƐƚƌĞƐƐ and protects dopaminergic neurons ŝŶ Ă ϲͲŚǇĚƌŽǆǇĚŽƉĂŵŝŶĞ ƌĂƚ ŵŽĚĞů ŽĨ Parkinsonism. Journal of neuroscience researchϮϬϬϱ͖ϴϭ;ϲͿ͗ϴϲϱͲϳϯ͘ ϱϰ͘ DƵŶŽǌ ͕ ZĞǇ W͕ 'ƵĞƌƌĂ D:͕ DĞŶĚĞǌͲ ůǀĂƌĞǌ ͕ ^ŽƚŽͲKƚĞƌŽ Z͕ >ĂďĂŶĚĞŝƌĂͲ 'ĂƌĐŝĂ :>͘ ZĞĚƵĐƟŽŶ ŽĨ ĚŽƉĂŵŝŶĞƌŐŝĐ ĚĞŐĞŶĞƌĂƟŽŶ ĂŶĚ ŽǆŝĚĂƟǀĞ ƐƚƌĞƐƐ ďǇ ŝŶŚŝďŝƟŽŶ ŽĨ ĂŶŐŝŽƚĞŶƐŝŶ ĐŽŶǀĞƌƟŶŐ ĞŶǌǇŵĞŝŶĂDWdWŵŽĚĞůŽĨƉĂƌŬŝŶƐŽŶŝƐŵ͘ NeuropharmacologyϮϬϬϲ͖ϱϭ;ϭͿ͗ϭϭϮͲϮϬ͘ ϱϱ͘ ZĞĂƌĚŽŶ <͕ DĞŶĚĞůƐŽŚŶ &͕ ŚĂŝ ^z͕ ,ŽƌŶĞ D<͘ dŚĞ ĂŶŐŝŽƚĞŶƐŝŶ ĐŽŶǀĞƌƟŶŐ ĞŶǌǇŵĞ ;Ϳ ŝŶŚŝďŝƚŽƌ͕ ƉĞƌŝŶĚŽƉƌŝů͕ ŵŽĚŝĮĞƐƚŚĞĐůŝŶŝĐĂůĨĞĂƚƵƌĞƐŽĨWĂƌŬŝŶƐŽŶ͛Ɛ disease. ƵƐƚƌĂůŝĂŶ ĂŶĚ EĞǁ ĞĂůĂŶĚ ũŽƵƌŶĂůŽĨŵĞĚŝĐŝŶĞϮϬϬϬ͖ϯϬ;ϭͿ͗ϰϴͲϱϯ͘ ϱϲ͘ >ŝŶ::͕zƵĞŚ<͕ŚĂŶŐ͕>ŝŶ^͘ƐƐŽĐŝĂƟŽŶ ďĞƚǁĞĞŶ ŐĞŶĞƟĐ ƉŽůǇŵŽƌƉŚŝƐŵ ŽĨ ĂŶŐŝŽƚĞŶƐŝŶͲĐŽŶǀĞƌƟŶŐ ĞŶǌǇŵĞ ŐĞŶĞ and Parkinson’s disease. Journal of the neurological sciencesϮϬϬϮ͖ϭϵϵ;ϭͲϮͿ͗ϮϱͲϵ͘ ϱϳ͘ >ŝŶ ::͕ zƵĞŚ <͕ >ŝŶ ^͕ ,ĂƌŶ ,:͕ >ŝƵ :d͘

'ĞŶĞƟĐƉŽůǇŵŽƌƉŚŝƐŵŽĨƚŚĞĂŶŐŝŽƚĞŶƐŝŶ ĐŽŶǀĞƌƟŶŐ ĞŶǌǇŵĞ ĂŶĚ >ͲĚŽƉĂͲŝŶĚƵĐĞĚ ĂĚǀĞƌƐĞ ĞīĞĐƚƐ ŝŶ WĂƌŬŝŶƐŽŶ͛Ɛ ĚŝƐĞĂƐĞ͘ Journal of the neurological sciencesϮϬϬϳ͖

252(2): 130-4.

ϱϴ͘ ^ŽŶŐ ''͕ >ĞĞ z,͘ dŚĞ ŝŶƐĞƌƟŽŶͬĚĞůĞƟŽŶ polymorphism in the angiotensin-ĐŽŶǀĞƌƟŶŐ ĞŶǌǇŵĞ ĂŶĚ ƐƵƐĐĞƉƟďŝůŝƚǇ ƚŽ ƐĐŚŝǌŽƉŚƌĞŶŝĂ Žƌ WĂƌŬŝŶƐŽŶ͛Ɛ ĚŝƐĞĂƐĞ͗ A meta-analysis. Journal of the renin-ĂŶŐŝŽƚĞŶƐŝŶͲĂůĚŽƐƚĞƌŽŶĞ ƐǇƐƚĞŵ ͗ :Z^ ϮϬϭϱ͖ϭϲ;ϮͿ͗ϰϯϰͲϰϮ͘

ϱϵ͘ ^Ƶ'͕ŽƵ,͕ŚĂŽ>͕ĞƚĂů͘dŚĞĂŶŐŝŽƚĞŶƐŝŶͲ ĐŽŶǀĞƌƟŶŐĞŶǌǇŵĞ;Ϳ/ͬƉŽůǇŵŽƌƉŚŝƐŵ in Parkinson’s disease. Journal of the renin-ĂŶŐŝŽƚĞŶƐŝŶͲĂůĚŽƐƚĞƌŽŶĞ ƐǇƐƚĞŵ ͗ :Z^ ϮϬϭϱ͖ϭϲ;ϮͿ͗ϰϮϴͲϯϯ͘ ϲϬ͘ ZĂǇW͕,ƵĂŶŐt͕dƐƵũŝz͘ZĞĂĐƟǀĞŽǆǇŐĞŶ ƐƉĞĐŝĞƐ ;ZK^Ϳ ŚŽŵĞŽƐƚĂƐŝƐ ĂŶĚ ƌĞĚŽǆ ƌĞŐƵůĂƟŽŶ ŝŶ ĐĞůůƵůĂƌ ƐŝŐŶĂůŝŶŐ͘ Cellular signallingϮϬϭϮ͖Ϯϰ;ϱͿ͗ϵϴϭͲϵϬ͘ ϲϭ͘ ,ĞƌŶĂŶĚĞƐ D^͕ ƌŝƩŽ >Z͘ EW, ŽǆŝĚĂƐĞ ĂŶĚ ŶĞƵƌŽĚĞŐĞŶĞƌĂƟŽŶ͘ Current neuropharmacologyϮϬϭϮ͖ϭϬ;ϰͿ͗ϯϮϭͲϳ͘ ϲϮ͘ <ŝŵ',͕<ŝŵ:͕ZŚŝĞ^:͕zŽŽŶ^͘dŚĞZŽůĞ ŽĨ KǆŝĚĂƟǀĞ ^ƚƌĞƐƐ ŝŶ EĞƵƌŽĚĞŐĞŶĞƌĂƟǀĞ Diseases. Experimental neurobiology ϮϬϭϱ͖Ϯϰ;ϰͿ͗ϯϮϱͲϰϬ͘

ϲϯ͘ DŽ:^͕<ŝŵDz͕ŶŶ:͕,ŽŶŐ:͕WĂƌŬ,^͘ :Ͳϭ ŵŽĚƵůĂƚĞƐ hsͲŝŶĚƵĐĞĚ ŽǆŝĚĂƟǀĞ stress signaling through the suppression ŽĨ D<<ϭ ĂŶĚ ĐĞůů ĚĞĂƚŚ͘ Ğůů ĚĞĂƚŚ ĂŶĚ ĚŝīĞƌĞŶƟĂƟŽŶϮϬϬϴ͖ϭϱ;ϲͿ͗ϭϬϯϬͲϰϭ͘ ϲϰ͘ DƵĚŽ '͕ DĂŬĞůĂ :͕ ŝ >ŝďĞƌƚŽ s͕ Ğƚ Ăů͘

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signalingϮϬϭϮ͖ϭϲ;ϭϬͿ͗ϭϬϯϯͲϰϱ͘

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dĂ ďůĞϮ͘ ŽŵŵŽŶǀ ĂƌŝĂŶ ƚĂƐƐŽĐŝĂ ƟŽŶƌ ĞƐƵůƚƐŽĨŐ ĞŶĞͲƐĞ ƚĂŶĂůǇ ƐŝƐŝŶ/W' t ^ĚĂ ƚĂƐĞ ƚ͘ AA changing ϭϬ ϮϬ Pa th w ay p (emp.) n va r p (emp.) n va r p (emp.) n va r Aut ophagy 0.374 10 0.405 4 0.355 1 Ca ve olar -media te d endocy tosis signaling Ϭ͘Ϭϯϰ;Ϭ͘ϬϱϰͿ 8 Ϭ͘Ϭϰϳ;Ϭ͘ϬϲϲͿ 5 0.250 2 Cla thrin-media te d endocy tosis signaling 0.348 21 0.154 14 0.758 6 Dŝƚ ŽĐŚŽŶĚƌŝĂůĚǇ ƐĨ ƵŶĐƟŽŶ 0.322 32 0.635 24 0.314 12 'ĂƉũƵŶĐƟŽŶƐŝŐŶĂůŝŶŐ 0.430 8 0.456 4 0.794 2 ŶŐŝŽƉŽŝĞƟŶƐŝŐŶĂůŝŶŐ 0.782 12 0.496 7 0.310 4 ŽƉĂŵŝŶĞͲ ZWWϯϮĨ ĞĞĚďĂĐŬŝŶĐDWƐŝŐŶĂůŝŶŐ 0.125 1 0.125 1 0.125 1 ^ŝŐŶĂůŝŶŐďǇƌŚŽĨ ĂŵŝůǇ'dW ĂƐĞƐ 0.347 18 0.377 14 0.785 11 ŵd KZƐŝŐŶĂůŝŶŐ 0.126 6 0.135 3 0.191 1 ,ƵŶ ƟŶŐ ƚŽŶ͛ ƐŝƐĞĂƐĞƐŝŐŶĂůŝŶŐ 0.579 32 0.452 16 0.359 9 ǆ ŽŶĂů'ƵŝĚĂŶĐĞƐŝŐŶĂůŝŶŐ 0.222 52 0.152 43 0.189 26 ZĞ ŶŝŶͲŶŐŝŽƚ ĞŶƐŝŶƐŝŐŶĂůŝŶŐ 0.086 6 0.074 4 Ϭ͘Ϭϯϯ;Ϭ͘ϬϱϰͿ 2 ZĂĐƐŝŐŶĂůŝŶŐ 0.308 13 0.544 9 0.453 5 ĐƟŶĐǇƚ ŽƐŬ ĞůĞ ƚŽŶƐŝŐŶĂůŝŶŐ 0.068 16 0.186 9 0.239 5 & <ƐŝŐŶĂůŝŶŐ 0.758 17 0.320 10 0.360 5 &> dϯƐŝŐŶĂůŝŶŐŝŶŚĞŵĂ ƚŽƉŽŝĞƟĐƉƌ ŽŐ ĞŶŝƚ ŽƌĐĞůůƐ 0.825 3 0.615 2 0.739 1 Cla thrin-media te d endocy tosis signaling 0.348 21 0.154 14 0.758 6 ǁ ĞŝŐŚ ƚĞĚ с ƐƵďƐĞƚ ŽĨ Ăůů Ğǆ ŽŶŝĐ ǀĂ ƌŝĂŶ ƚƐ ǁ ĞŝŐŚ ƚĞĚ ŽŶ ƵŶƐĐ ĂůĞĚ ͲƐĐ Žƌ ĞƐ͖ ĐŚĂŶŐŝŶŐ с ĂŵŝŶŽ ĂĐŝĚ ĐŚĂŶŐŝŶŐ ƐƵďƐĞƚ͖ ϭϬ с ƐƵďƐĞ ƚ ŽĨ ǀ ĂƌŝĂŶ ƚƐ Ɖƌ ĞĚŝĐƚ ĞĚ ƚŽ ď ĞůŽŶŐ ƚŽ ϭϬй ŵŽƐ ƚ ĚĞůĞƚ ĞƌŝŽƵƐ ǀĂƌŝĂŶ ƚƐ ŽĨ ƚŚĞ ŐĞŶŽŵĞ͖ ϮϬ с ƐƵďƐĞ ƚ ŽĨ ǀĂ ƌŝĂŶ ƚƐ Ɖ ƌĞ ĚŝĐƚ ĞĚ ƚŽ ďĞůŽŶŐ ƚŽ ϭй ŵŽƐ ƚ ĚĞůĞƚ ĞƌŝŽƵƐ ǀĂƌŝĂŶ ƚƐ ŽĨ ŐĞŶŽŵĞ ͖ĚŝƐƌƵƉƟǀ Ğ с ƐƵďƐĞ ƚ ŽĨ ůŽƐƐͲŽĨ ͲĨƵŶĐƟŽŶ ǀĂ ƌŝĂŶ ƚƐ͘ p (emp) = nominal

p-value with empiric

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dĂ ďůĞϯ͘ ŽŵŵŽŶǀ ĂƌŝĂŶ ƚĂƐƐŽĐŝĂ ƟŽŶŽĨ renin-angiot ensin and ĐĂ ǀĞŽůĂƌ ͲŵĞĚŝĂƚ ĞĚĞŶĚŽĐǇƚ ŽƐŝƐƐŝŐŶĂůŝŶŐ pa th w ay . /W' MER CK PPMI Pa th w ay varian t type p(emp) n v ar p(emp) n v ar p(emp) n v ar ZĞ ŶŝŶĂŶŐŝŽƚ ĞŶƐŝŶ AA changing 0.086 6 0.198 5 0.756 3 (c ommon v arian ts) CADD10 0.074 4 0.267 4 0.666 1 CADD20 Ϭ͘Ϭϯϯ;Ϭ͘ϬϱϰͿ 2 Ϭ͘ϬϰϬ;Ϭ͘ϬϰϵͿ 2N A N A Ca ve olar -media te d endocy tosis AA changing Ϭ͘Ϭϭϰ;Ϭ͘ϬϮϱͿ 219 0.345 12 0.087 21 (c ommon and r ar e v arian ts) CADD10 Ϭ͘ϬϰϬ;Ϭ͘ϬϳϬͿ 172 0.299 9 Ϭ͘ϬϮϰ;Ϭ͘ϬϮϰͿ 14 CADD20 0.13 136 0.351 4 0.163 8 ĐŚĂŶŐŝŶŐ с ĂŵŝŶŽ ĂĐŝĚ ĐŚĂŶŐŝŶŐ ƐƵďƐĞƚ͖ ϭϬ с ƐƵďƐĞƚ ŽĨ ǀĂ ƌŝĂŶ ƚƐ Ɖƌ ĞĚŝĐƚ ĞĚ ƚŽ ď ĞůŽŶŐ ƚŽ ϭϬй ŵ ŽƐ ƚĚĞůĞƚ ĞƌŝŽƵƐ ǀĂƌŝĂŶ ƚƐ ŽĨ ƚŚĞ ŐĞ ŶŽŵĞ͖ ϮϬ с ƐƵďƐĞƚ ŽĨ ǀĂ ƌŝĂŶ ƚƐ Ɖƌ ĞĚŝĐƚ ĞĚ ƚŽ ďĞůŽŶŐ ƚŽ ϭйŵŽƐ ƚĚĞůĞ ƚĞƌŝŽƵƐǀ ĂƌŝĂŶ ƚƐŽĨŐ ĞŶŽŵĞ͖ p (emp) = nominal

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dĂ ďůĞϰ͘ ŽŵŵŽŶĂŶĚƌ Ăƌ Ğǀ ĂƌŝĂŶ ƚĂƐƐŽĐŝĂ ƟŽŶƌ ĞƐƵůƚƐŽĨŐ ĞŶĞͲƐĞ ƚĂŶĂůǇ ƐŝƐ ŝŶ/W't ^ĚĂ ƚĂ ƐĞ ƚ͘ AA changing ϭϬ ϮϬ Pa th w ay p (emp.) n va r p (emp.) n va r p (emp.) n va r Aut ophagy 0.623 356 0.707 315 0.637 238 Ca ve olar -media te d endocy tosis signaling Ϭ͘Ϭϭϰ;Ϭ͘ϬϮϱͿ 219 Ϭ͘ϬϰϬ;Ϭ͘ϬϳϬͿ 172 0.130 136 Cla thrin-media te d endocy tosis signaling 0.083 783 0.086 668 0.115 516 Dŝƚ ŽĐŚŽŶĚƌŝĂůĚǇ ƐĨ ƵŶĐƟŽŶ Ϭ͘ϬϬϴϭ;Ϭ͘ϭϲϵͿ 911 Ϭ͘ϬϬϮϱ;Ϭ͘ϬϴϱͿ 805 Ϭ͘ϬϬϭϰ;Ϭ͘ϬϰϳͿ 651 'ĂƉũƵŶĐƟŽŶƐŝŐŶĂůŝŶŐ Ϭ͘Ϭϰϯ;Ϭ͘ϬϳϵͿ 267 0.114 214 0.345 159 ŶŐŝŽƉŽŝĞƟŶƐŝŐŶĂůŝŶŐ 0.352 386 0.158 337 0.058 253 ŽƉĂŵŝŶĞͲ ZWWϯϮĨ ĞĞĚďĂĐŬŝŶĐDWƐŝŐŶĂůŝŶŐ 0.067 141 Ϭ͘Ϭϯϰ;Ϭ͘ϬϰϱͿ 125 0.125 97 ^ŝŐŶĂůŝŶŐďǇƌŚŽĨ ĂŵŝůǇ'dW ĂƐĞƐ 0.633 519 0.584 461 0.693 367 ŵd KZƐŝŐŶĂůŝŶŐ 0.282 371 0.301 329 0.321 245 ,ƵŶ ƟŶŐ ƚŽŶ͛ ƐŝƐĞĂƐĞƐŝŐŶĂůŝŶŐ 0.407 930 0.169 801 0.079 592 ǆ ŽŶĂůŐƵŝĚĂŶĐĞƐŝŐŶĂůŝŶŐ 0.241 1450 0.136 1275 0.237 969 ZĞ ŶŝŶͲĂŶŐŝŽƚ ĞŶƐŝŶƐŝŐŶĂůŝŶŐ 0.187 333 0.071 282 0.100 209 ZĂĐƐŝŐŶĂůŝŶŐ 0.588 491 0.869 431 0.709 339 ĐƟŶĐǇƚ ŽƐŬ ĞůĞ ƚŽŶƐŝŐŶĂůŝŶŐ 0.185 633 0.417 538 0.350 427 & <ƐŝŐŶĂůŝŶŐ 0.613 375 0.352 323 0.392 242 &> dϯƐŝŐŶĂůŝŶŐŝŶŚĞŵĂ ƚŽƉŽŝĞƟĐƉƌ ŽŐ ĞŶŝƚ ŽƌĐĞůůƐ 0.635 186 0.612 165 0.863 114 Cla thrin-media te d endocy tosis signaling 0.083 783 0.086 668 0.115 516 ǁ ĞŝŐŚ ƚĞĚ с ƐƵďƐĞƚ ŽĨ Ăůů Ğǆ ŽŶŝĐ ǀĂ ƌŝĂŶ ƚƐ ǁ ĞŝŐŚ ƚĞĚ ŽŶ ƵŶƐĐ ĂůĞĚ ͲƐĐ Žƌ ĞƐ͖ ĐŚĂŶŐŝŶŐ с ĂŵŝŶŽ ĂĐŝĚ ĐŚĂŶŐŝŶŐ ƐƵďƐĞƚ͖ ϭϬ с ƐƵďƐĞ ƚ ŽĨ ǀ ĂƌŝĂŶ ƚƐ Ɖƌ ĞĚŝĐƚ ĞĚ ƚŽ ď ĞůŽŶŐ ƚŽ ϭϬй ŵŽƐ ƚ ĚĞůĞƚ ĞƌŝŽƵƐ ǀĂƌŝĂŶ ƚƐ ŽĨ ƚŚĞ ŐĞŶŽŵĞ͖ ϮϬ с ƐƵďƐĞ ƚ ŽĨ ǀĂ ƌŝĂŶ ƚƐ Ɖ ƌĞ ĚŝĐƚ ĞĚ ƚŽ ďĞůŽŶŐ ƚŽ ϭй ŵŽƐ ƚ ĚĞůĞƚ ĞƌŝŽƵƐ ǀĂƌŝĂŶ ƚƐ ŽĨ ŐĞŶŽŵĞ ͖ĚŝƐƌƵƉƟǀ Ğ с ƐƵďƐĞ ƚ ŽĨ ůŽƐƐͲŽĨ ͲĨƵŶĐƟŽŶ ǀĂ ƌŝĂŶ ƚƐ͘ p (emp) = nominal

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dĂďůĞϱ͘/ŶĚŝǀŝĚƵĂůŐĞŶĞĂƐƐŽĐŝĂƟŽŶƐĨŽƌŵŝƚŽĐŚŽŶĚƌŝĂůĚǇƐĨƵŶĐƟŽŶ͘ Gene p ;ĞŵƉ͘Ϳ n var >ŽĐĂƟŽŶ /W' CASP9 0.029 (0.021) 17 cytoplasm &hZ/E 0.00045 (0.0002) 19 cytoplasm Kyϰ/ϭ 0.006 (0.0035) 7 ĐŽŵƉůĞǆϰ Eh&ϯ 0.041 (0.071) 3 ĐŽŵƉůĞǆϭ ATP5J 0.0023 (0.0003) 4 ĐŽŵƉůĞǆϱ ATP5O 0.035 (0.030) 17 ĐŽŵƉůĞǆϱ SDHA 0.0059 (0.0078) 42 ĐŽŵƉůĞǆϮ DZ< Eh&^ϱ 0.033 (0.036) 1 ĐŽŵƉůĞǆϭ Eh&sϭ 0.00001 (0.0001) 2 ĐŽŵƉůĞǆϭ PPMI Eh&^ϴ 0.045 (0.059) 2 ĐŽŵƉůĞǆϭ Eh&ϵ 0.0002 (0.0008) 1 ĐŽŵƉůĞǆϭ Eh&ϱ 0.011 (0.018) 1 ĐŽŵƉůĞǆϭ Kyϲ 0.012 (0.015) 2 ĐŽŵƉůĞǆϰ

p (emp) = nominal p-value with empirical pͲǀĂůƵĞŝŶƉĂƌĞŶƚŚĞƐŝƐŽĨǁŚŝĐŚƚŚĞůĂƩĞƌǁĂƐĐĂůĐƵůĂƚĞĚďǇĐŽŵƉĂƌŝƐŽŶƚŽϭϬ͕ϬϬϬ ƉĞƌŵƵƚĂƟŽŶƐŽĨĂīĞĐƟŽŶƐƚĂƚƵƐ͘

dĂďůĞϲ͘^ŝŶŐůĞǀĂƌŝĂŶƚƐƚĂƟƐƟĐƐŽĨƌĞŶŝŶͲĂŶŐŝŽƚĞŶƐŝŶƐŝŐŶĂůŝŶŐƉĂƚŚǁĂǇ͘

ĂƚĂƐĞƚ Gene WŽƐŝƟŽŶ sĂƌƚǇƉĞ MAF cases D&ĐŽŶƚƌŽůƐ

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DZ<

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