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Cracking the code-ing sequence for Parkinson’s disease

Jansen, I.E.

2017

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

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CHAPTER 7

General Discussion

7

WĂƌŬŝŶƐŽŶ͛Ɛ ĚŝƐĞĂƐĞ ;WͿ ŝƐ Ă ŶĞƵƌŽĚĞŐĞŶĞƌĂƟǀĞ ĚŝƐĞĂƐĞ ƚŚĂƚ ƐƟůů ĂǁĂŝƚƐ ƐƵĐĐĞƐƐĨƵů treatment slowing, altering or reversing the disease progression. The current available therapies only diminish the clinical symptoms and are not modifying the underlying ĚŝƐĞĂƐĞ ƉĂƚŚŽůŽŐLJ͘ ZĞƐĞĂƌĐŚ ƐƚƵĚLJŝŶŐ ƚŚĞ ĨƵŶĚĂŵĞŶƚĂů ƉƌŽƉĞƌƟĞƐ ŽĨ ƚŚĞ ĚŝƐĞĂƐĞ ĐŽŶƚƌŝďƵƚĞƐ ƚŽ ŽƵƌ ƵŶĚĞƌƐƚĂŶĚŝŶŐ ŽĨ ƚŚĞ ďŝŽůŽŐŝĐĂů ƉƌŽĐĞƐƐĞƐ ĐĂƵƐŝŶŐ W͘ KŶĐĞ ƚŚĞ W ĮĞůĚĐŽŵƉƌĞŚĞŶĚƐƚŚĞŽƌŝŐŝŶĂŶĚƉƌŽŐƌĞƐƐŝŽŶŽĨƚŚĞĚŝƐĞĂƐĞŽŶĂĚĞƚĂŝůĞĚƉĂƚŚŽůŽŐŝĐĂů and molecular biological level, it will enable the development of improved therapies as ƚĂƌŐĞƚƐĨŽƌĚƌƵŐƐĂƌĞŵŽƌĞĂĐĐƵƌĂƚĞůLJĚĞĮŶĞĚ͘'ĞŶĞƟĐƐƉůĂLJƐĂŵĂũŽƌƌŽůĞŝŶƚŚĞŽŶƐĞƚ of PD.1_{ŽnjĞŶƐŽĨĐŽŵŵŽŶƌŝƐŬůŽĐŝǁŝƚŚŵŽĚĞƌĂƚĞĞīĞĐƚĂŶĚƌĂƌĞǀĂƌŝĂŶƚƐǁŝƚŚĂŚŝŐŚ}

ƉĞŶĞƚƌĂŶĐĞŚĂǀĞďĞĞŶůŝŶŬĞĚƚŽW͘,ŽǁĞǀĞƌ͕ƐƟůůŽŶůLJƵƉƚŽϱϬйŽĨƚŚĞŐĞŶĞƟĐǀĂƌŝĂƟŽŶ ĐĂŶďĞĞdžƉůĂŝŶĞĚďLJƚŚĞƐĞWͲƌĞůĂƚĞĚŐĞŶĞƟĐĨĂĐƚŽƌƐ͘2,3_{dŚĞŝĚĞŶƟĮĐĂƟŽŶŽĨŶŽǀĞůŐĞŶĞƟĐ}

variants, and a more detailed understanding of PD-related genes, will help to improve our ŬŶŽǁůĞĚŐĞŽĨWƉĂƚŚŽŐĞŶĞƐŝƐ͘ZĞƐĞĂƌĐŚŚĂƐƐŚŽǁŶƚŚĂƚWŐĞŶĞƐĐŽŶǀĞƌŐĞŽŶŵƵůƟƉůĞ ďŝŽůŽŐŝĐĂů ƉƌŽĐĞƐƐĞƐ ĂŶĚ ŶŽǀĞů ŐĞŶĞƐ ǁŝůů ƉŽƚĞŶƟĂůůLJ ƉŽŝŶƚ ƚŽ ĂĚĚŝƟŽŶĂů ĚLJƐĨƵŶĐƟŽŶĂů molecular pathways.4 _{As PD is a heterogeneous disease on a clinical, pathological and}

ŐĞŶĞƟĐůĞǀĞů͕ŝƚŝƐĂŶƟĐŝƉĂƚĞĚƚŚĂƚƚŚĞƌĂƉŝĞƐ͕ĂƉĂƌƚĨƌŽŵƉĞƌƐŽŶĂůŵĞĚŝĐŝŶĞĨŽƌŝŶĚŝǀŝĚƵĂůƐ ǁŝƚŚŵŽŶŽŐĞŶŝĐW͕ƚĂƌŐĞƟŶŐĐŽŵŵŽŶƵŶĚĞƌůLJŝŶŐďŝŽůŽŐŝĐĂůƉĂƚŚǁĂLJƐǁŝůůƉƌŽďĂďůLJďĞ ďĞŶĞĮĐŝĂůƚŽƚƌĞĂƚŵƵůƟƉůĞŐƌŽƵƉƐŽĨWƉĂƟĞŶƚƐǁŝƚŚĚŝƐƟŶĐƚƵŶĚĞƌůLJŝŶŐŐĞŶĞƟĐĐĂƵƐĞƐ͘ dŽŝŵƉƌŽǀĞŽƵƌƵŶĚĞƌƐƚĂŶĚŝŶŐŽĨƚŚĞŐĞŶĞƟĐĨĂĐƚŽƌƐĐŽŶƚƌŝďƵƟŶŐƚŽW͕ǁĞƵƐĞĚ ǁŚŽůĞĞdžŽŵĞƐĞƋƵĞŶĐŝŶŐ;t^Ϳ͕ĂŶĞdžƚͲŐĞŶĞƌĂƟŽŶƐĞƋƵĞŶĐŝŶŐ;E'^ͿƚĞĐŚŶŝƋƵĞĨŽĐƵƐŝŶŐ ŽŶƚŚĞĐŽĚŝŶŐƌĞŐŝŽŶƐŽĨƚŚĞŐĞŶŽŵĞ͘tŝƚŚƚŚĞŝŶƚƌŽĚƵĐƟŽŶŽĨE'^ŝŶƚŚĞĮƌƐƚĚĞĐĂĚĞ of the 21st_{ĐĞŶƚƵƌLJ͕ŝƚďĞĐĂŵĞĂƐƚĂŶĚĂƌĚĂƉƉƌŽĂĐŚƚŽĨŽĐƵƐŽŶƌĂƌĞǀĂƌŝĂŶƚƐ͕ĂŶƟĐŝƉĂƟŶŐ} ƚŚĞĚŝƐĐŽǀĞƌLJŽĨŶŽǀĞůŐĞŶĞƟĐǀĂƌŝĂŶƚƐƚŚĂƚǁŽƵůĚĞůƵĐŝĚĂƚĞƚŚĞƌĞŵĂŝŶŝŶŐƵŶĞdžƉůĂŝŶĞĚ ŚĞƌŝƚĂďŝůŝƚLJ͘tŚĞƌĞ't^ŚĂĚƉƌĞǀŝŽƵƐůLJĚŽŵŝŶĂƚĞĚƚŚĞŐĞŶĞƟĐƐƌĞƐĞĂƌĐŚĮĞůĚǁŝƚŚƚŚĞ ŝĚĞŶƟĮĐĂƟŽŶŽĨĐŽŵŵŽŶƌŝƐŬĨĂĐƚŽƌƐ͕ƚŚĞE'^ƚĞĐŚŶŽůŽŐLJĂůůŽǁĞĚƚŚĞŝŶǀĞƐƟŐĂƟŽŶŽĨ ƌĂƌĞǀĂƌŝĂŶƚƐ͕ƚŚĞƌĞďLJĐĂƵƐŝŶŐĂƐŚŝŌƚŽǁĂƌĚƐĂŶŝŶƚĞƌĞƐƚŝŶƚŚĞŐĞŶĞƟĐŝŶŇƵĞŶĐĞŽĨƌĂƌĞ ǀĂƌŝĂŶƚƐŽŶĚŝƐĞĂƐĞƐ͘dŚĞƐĐŝĞŶƟĮĐǁŽƌŬƉĞƌĨŽƌŵĞĚĨŽƌƚŚŝƐƚŚĞƐŝƐǁĂƐƐƚĂƌƚĞĚĂƚĂƟŵĞ point when a large number of common risk loci for PD were established. Therefore, by ƵƐŝŶŐt^͕ĂŶĚƚŚĞƌĞďLJĞdžƉůŽƌŝŶŐƚŚĞƌĂƌĞƌǀĂƌŝĂŶƚƐ͕ŝƚǁĂƐĞdžƉĞĐƚĞĚƚŚĂƚŶŽǀĞůWͲƌĞůĂƚĞĚ ŐĞŶĞƟĐĨĂĐƚŽƌƐǁŽƵůĚďĞƌĞǀĞĂůĞĚ͘

^hDDZz

tŝƚŚŝŶƚŚŝƐƚŚĞƐŝƐǁĞŚĂǀĞĞƐƚĂďůŝƐŚĞĚƚŚĞĐŽŶƚƌŝďƵƟŽŶŽĨŬŶŽǁŶWŐĞŶĞƐŝŶŵŽƌĞĚĞƚĂŝů ĂŶĚ ƐĞĂƌĐŚĞĚ ĨŽƌ ŶŽǀĞů ŽŶĞƐ͘ dŽ ĨƵƌƚŚĞƌ ĞdžƉůŽƌĞ ƚŚĞ ŬŶŽǁŶ ŐĞŶĞƐ͕ ƚǁŽ /W' ĞdžŽŵĞ ĚĂƚĂƐĞƚƐ ǁĞƌĞ ĂĐĐĞƐƐĞĚ ĨŽƌ ǀĂůŝĚĂƟŽŶ ŽĨ ƚŚĞ ŶŽǀĞů DĞŶĚĞůŝĂŶ W ŐĞŶĞ CHCHD2 and ĨŽƌĚĞƚĞƌŵŝŶŝŶŐƚŚĞĞīĞĐƚŽĨƌĂƌĞŐĞŶĞƟĐǀĂƌŝĂŶƚƐǁŝƚŚŝŶƚŚĞƉƵďůŝƐŚĞĚWƌŝƐŬůŽĐŝ͘&Žƌ CHCHD2 (chapter 2), ĂŐĞŶĞŝŶǀŽůǀĞĚŝŶŵŝƚŽĐŚŽŶĚƌŝĂůĨƵŶĐƟŽŶǁŚŝĐŚǁĂƐĮƌƐƚŽďƐĞƌǀĞĚ

7

ƵƌŽƉĞĂŶƉŽƉƵůĂƟŽŶ͘KŶĞŝĚĞŶƟĐĂůĐŽŵŵŽŶǀĂƌŝĂŶƚƚŽĂƐŝŐŶŝĮĐĂŶƚ^EWŝŶƚŚĞŽƌŝŐŝŶĂů ƐŝĂŶƐƚƵĚLJǁĂƐŶŽƚĂƐƐŽĐŝĂƚĞĚŝŶŽƵƌEĞƵƌŽyĚĂƚĂƐĞƚ͕ƐƵŐŐĞƐƟŶŐƐŝĂŶͲƐƉĞĐŝĮĐŝƚLJĨŽƌƚŚĂƚ ƉĂƌƟĐƵůĂƌǀĂƌŝĂŶƚ͘ůƚŚŽƵŐŚǁĞĚŝĚŶŽƚŽďƐĞƌǀĞĂŶĂƐƐŽĐŝĂƟŽŶŽĨĐŽŵŵŽŶǀĂƌŝĂŶƚƐ͕ϯƌĂƌĞ ŶŽŶƐLJŶŽŶLJŵŽƵƐǀĂƌŝĂŶƚƐ;D&чϬ͘ϬϬϬϴͿǁĞƌĞŽďƐĞƌǀĞĚŝŶϰĐĂƐĞƐǁŚŝůĞŶŽƚĂƐŝŶŐůĞƌĂƌĞ variant was observed in healthy controls. These results suggest that CHCHD2 could also ďĞĂƌĂƌĞƌŝƐŬĨĂĐƚŽƌŝŶƚŚĞƵƌŽƉĞĂŶƉŽƉƵůĂƟŽŶ͕ďƵƚŵŽƌĞĞdžƚĞŶƐŝǀĞƐĞƋƵĞŶĐŝŶŐƌĞƐĞĂƌĐŚ ŝŶǀŽůǀŝŶŐůĂƌŐĞƌĚĂƚĂƐĞƚƐƐŚŽƵůĚďĞƉĞƌĨŽƌŵĞĚƚŽĞŶĂďůĞĂŶLJĚĞĮŶŝƟǀĞĐŽŶĐůƵƐŝŽŶƐ͘

DƵůƟƉůĞŐĞŶŽŵĞͲǁŝĚĞĂƐƐŽĐŝĂƟŽŶƐƚƵĚŝĞƐŚĂǀĞůŝŶŬĞĚĚŽnjĞŶƐŽĨĐŽŵŵŽŶůŽĐŝƚŽ the risk of developing PD.6-9_{LJƵƐŝŶŐŽƵƌĞdžŽŵĞĚĂƚĂƐĞƚƐ͕ǁĞƚĞƐƚĞĚ whether rare coding}

ǀĂƌŝĂŶƚƐǁŝƚŚŝŶƚŚĞƐĞŬŶŽǁŶƌŝƐŬůŽĐŝŵŝŐŚƚĂůƐŽŝŶŇƵĞŶĐĞĚŝƐĞĂƐĞƌŝƐŬ;chapter 3Ϳ͘&Žƌ the analysis of single rare variants large datasets with tens of thousands of individuals ĂƌĞ ƌĞƋƵŝƌĞĚ ƚŽ ƌĞĂĐŚ ƐƵĸĐŝĞŶƚ ƐƚĂƟƐƟĐĂů ƉŽǁĞƌ͘ dŽ ŝŶĐƌĞĂƐĞ ƚŚŝƐ ƉŽǁĞƌ ǁĞ ƚŚĞƌĞĨŽƌĞ ĂŐŐƌĞŐĂƚĞĚƌĂƌĞǀĂƌŝĂŶƚƐƉĞƌŐĞŶĞĂŶĚŐĞŶĞͲƐĞƚƚŽƚĞƐƚĨŽƌƚŚĞŝƌũŽŝŶƚĞīĞĐƚŽĨƌĂƌĞǀĂƌŝĂŶƚƐ ŽŶW͘Ɛ't^ƌŝƐŬůŽĐŝŝŶĚŝĐĂƚĞƌĞŐŝŽŶƐŝŶǁŚŝĐŚǀĂƌŝĂŶƚƐĂƌĞŝŶůŝŶŬĂŐĞĚŝƐĞƋƵŝůŝďƌŝƵŵ ;>ͿƚŚĂƚĨƌĞƋƵĞŶƚůLJĞŶĐŽŵƉĂƐƐŵƵůƟƉůĞŐĞŶĞƐŽĨǁŚŝĐŚƚŚĞĐĂƵƐĂůŐĞŶĞŝƐƵŶĚĞĮŶĞĚ͕ ǁĞ ƵƐĞĚ Ă ƐƚƌĂƚĞŐLJ ;Wƌŝdž&ŝdžĞͿ ƚŚĂƚ ƐĞůĞĐƚĞĚ ƚŚĞ ŵŽƐƚ ƉƌŽďĂďůĞ ĐĂƵƐĂů ŐĞŶĞ ďĂƐĞĚ ŽŶ ƵŶĚĞƌůLJŝŶŐĨƵŶĐƟŽŶĂůƐŝŵŝůĂƌŝƟĞƐ͘tĞĐŽŶĮƌŵĞĚƚŚĞĂƐƐŽĐŝĂƟŽŶŽĨƚŚĞǁĞůůͲĞƐƚĂďůŝƐŚĞĚ LRRK2 ĐŽŶĐĞƌŶŝŶŐ ďŽƚŚ ĐŽŵŵŽŶ ĂŶĚ ƌĂƌĞ ǀĂƌŝĂŶƚ ĂƐƐŽĐŝĂƟŽŶƐ͘ &ƵƌƚŚĞƌŵŽƌĞ͕ STBD1

and SPATA19 ƐŚŽǁĂŶĂƐƐŽĐŝĂƟŽŶƚŽWŝŶƚŚĞt^ĂŶĚEĞƵƌŽyĚĂƚĂƐĞƚƐ͕ƌĞƐƉĞĐƟǀĞůLJ͘ dŚĞŐĞŶĞͲƐĞƚĂŐŐƌĞŐĂƟŽŶĂƉƉƌŽĂĐŚĚĞƚĞĐƚĞĚ͕ĂƐĂŶƟĐŝƉĂƚĞĚ͕ĂŵŽĚĞƌĂƚĞĂƐƐŽĐŝĂƟŽŶŽĨ ĐŽŵŵŽŶǀĂƌŝĂŶƚƐ͘,ŽǁĞǀĞƌ͕ƚŚĞƌĞǁĂƐŶŽĞīĞĐƚŽĨĂŐŐƌĞŐĂƚĞĚƌĂƌĞǀĂƌŝĂŶƚƐǁŚĞŶƚĞƐƟŶŐ ƚŚĞŐĞŶĞͲƐĞƚ͘/ƚŝƐĐŽŵƉůŝĐĂƚĞĚƚŽĐŽŶĐůƵĚĞǁŚĞƚŚĞƌƚŚŝƐŝƐĚƵĞƚŽĂŶŝŶĐŽƌƌĞĐƚƐĞůĞĐƟŽŶŽĨ ĐĂƵƐĂůŐĞŶĞƐďLJƚŚĞWƌŝdž&ŝdžĞĂƉƉƌŽĂĐŚŽƌǁŚĞƚŚĞƌƌĂƌĞǀĂƌŝĂŶƚƐŝŶWƌŝƐŬůŽĐŝĂƌĞŐĞŶƵŝŶĞůLJ ŶŽƚĐŽŶƚƌŝďƵƟŶŐƚŽWƌŝƐŬ͘dŚŝƐĐŚĂƉƚĞƌĐůĞĂƌůLJƐŚŽǁƐƚŚĞŶĞĞĚĨŽƌŝŵƉƌŽǀĞĚĨƵŶĐƟŽŶĂů ƉƌŝŽƌŝƟnjĂƟŽŶƚŽŽůƐ͕ďĞƐŝĚĞƐWƌŝdž&ŝdžĞ͕ƚŚĂƚĂƌĞĂďůĞƚŽĂĚĞƋƵĂƚĞůLJĐĂůůƚŚĞŵŽƐƚƉƌŽďĂďůLJ gene(s) while taking into account the biological features of the disease of interest.

7

ĂƐƐŽĐŝĂƟŽŶƐ ĨŽƌ GBA͕ ǁŚŝĐŚ ĐŽŶĮƌŵƐ ƚŚĞ ƐƚƌĞŶŐƚŚ ŽĨ ŽƵƌ ƐƚƵĚLJ ĚĞƐŝŐŶ͘ KƵƌ ƌĞƐƵůƚƐ ĨƵƌƚŚĞƌŵŽƌĞƐƵŐŐĞƐƚƚŚĂƚŵƵůƟƉůĞǀĂƌŝĂŶƚƐŝŶǀĂƌŝŽƵƐ>^ŐĞŶĞƐǁŝƚŚŝŶĂƐŝŶŐůĞŝŶĚŝǀŝĚƵĂů͕ ƚŚĞƐŽĐĂůůĞĚŽůŝŐŽŐĞŶŝĐĞīĞĐƚ͕ŵŝŐŚƚŝŶĐƌĞĂƐĞƚŚĞƌŝƐŬĨŽƌW͘&ŝŶĂůůLJ͕GBA, SMPD1, CTSD and SLC17A5 ƐŚŽǁŝŶĚĞƉĞŶĚĞŶƚƐŝŐŶŝĮĐĂŶƚĞīĞĐƚƐŽŶW͕ŽĨǁŚŝĐŚƚŚĞĮƌƐƚϮŐĞŶĞƐŚĂǀĞ ĂůƌĞĂĚLJďĞĞŶĚŝƐĐƵƐƐĞĚŝŶƚŚĞĐŽŶƚĞdžƚŽĨWƌŝƐŬŝŶůŝƚĞƌĂƚƵƌĞ͘KǀĞƌĂůů͕ǁĞĐŽŶĐůƵĚĞƚŚĂƚ ĂĚĚŝƟŽŶĂůŶŽŶͲGBAǀĂƌŝĂŶƚƐŝŶ>^ŐĞŶĞƐĐŽŶƚƌŝďƵƚĞƚŽWƐƵƐĐĞƉƟďŝůŝƚLJǁŚĞƌĞƚŚĞĞīĞĐƚƐ ŵŝŐŚƚďĞĐŽŶƐŝƐƚĞŶƚǁŝƚŚĂŵŽĚĞůŽĨŽůŝŐŽŐĞŶŝĐƌŝƐŬĨĂĐƚŽƌƐ͘ĚĚŝƟŽŶĂůƐĞƋƵĞŶĐŝŶŐŝŶůĂƌŐĞƌ ƐĂŵƉůĞƐŝnjĞƐĂŶĚĨƵŶĐƟŽŶĂůĨŽůůŽǁͲƵƉƐƚƵĚŝĞƐƐŚŽƵůĚĨƵƌƚŚĞƌŝŶǀĞƐƟŐĂƚĞƚŚĞĞdžĂĐƚƌŽůĞŽĨ these LSD genes in PD pathogenesis.

A second approach based gene-sets of interest on biological processes that are ĂīĞĐƚĞĚŝŶWƉĂƚŚŽďŝŽůŽŐLJ;chapter 5Ϳ͕ĞŝƚŚĞƌďĂƐĞĚŽŶůŝƚĞƌĂƚƵƌĞŽƌŽŶŐĞŶĞͲĞdžƉƌĞƐƐŝŽŶ research.4,10_{ dŚĞ ůĂƩĞƌ ŝŶǀŽůǀĞĚ Ă ŐĞŶŽŵĞͲǁŝĚĞ ƚƌĂŶƐĐƌŝƉƚŽŵŝĐƐ ƐƚƵĚLJ ƚŚĂƚ ŝĚĞŶƟĮĞĚ} ƐƉĞĐŝĮĐ ďŝŽůŽŐŝĐĂů ƉĂƚŚǁĂLJƐ ďĂƐĞĚ ŽŶ ĚŝīĞƌĞŶĐĞƐ ŝŶ ŐĞŶĞͲĞdžƉƌĞƐƐŝŽŶ ůĞǀĞůƐ Ăƚ ĚŝƐƟŶĐƚ ůĞǀĞůƐ ŽĨ ƌĂĂŬ ƐƚĂŐĞ ɲͲƐLJŶƵĐůĞŝŶ ƉĂƚŚŽůŽŐLJ ďLJ ƵƐŝŶŐ ƉŽƐƚͲŵŽƌƚĞŵ ďƌĂŝŶ ƐĂŵƉůĞƐ͘ LJ ƐƉĞĐŝĮĐĂůůLJŝŶǀĞƐƟŐĂƟŶŐƚŚĞĂīĞĐƚĞĚŵŽůĞĐƵůĂƌƉƌŽĐĞƐƐĞƐŽĨƌĂĂŬƐƚĂŐĞƐϭĂŶĚϮ͕ƚŚĞ ƉƌĞͲƐLJŵƉƚŽŵĂƟĐƐƚĂŐĞ͕ǁĞĂŝŵĞĚƚŽĚĞƚĞƌŵŝŶĞǁŚĞƚŚĞƌƚŚĞƐĞŽďƐĞƌǀĞĚŐĞŶĞĞdžƉƌĞƐƐŝŽŶ ĐŚĂŶŐĞƐ ĐŽƵůĚ ďĞ ĐĂƵƐĞĚ ďLJ ŐĞŶĞƟĐ ĚĞĨĞĐƚƐ͘ dŚƌĞĞ ďŝŽůŽŐŝĐĂů ƉĂƚŚǁĂLJƐ ;ŵŝƚŽĐŚŽŶĚƌŝĂů

ĚLJƐĨƵŶƟŽŶ͕ ĐĂǀĞŽůĂƌͲŵĞĚŝĂƚĞĚ ĞŶĚŽĐLJƚŽƐŝƐ ƐŝŐŶĂůŝŶŐ and renin-angiotensin signaling)

7

frequency in our PD cohort, of which 'Wd,Ϯ>͕h,Z&ϭWϭ>͕WdWZ,͕Z^ and VPS13C ŐĞŶĞƐ ƐŚŽǁ ĐŽŶǀŝŶĐŝŶŐ WͲƌĞůĂƚĞĚ ƉŚĞŶŽƚLJƉĞƐ ŝŶ ĨƵŶĐƟŽŶĂů ĞdžƉĞƌŝŵĞŶƚƐ ĂŶĚ ŐĞŶĞƟĐ ĐŽŶĮƌŵĂƟŽŶ ŝŶ ŝŶĚĞƉĞŶĚĞŶƚ W ĚĂƚĂƐĞƚƐ͘ dŚĞ ŝĚĞŶƟĮĐĂƟŽŶ ŽĨ ƚŚĞ W ŐĞŶĞ VPS13C ĞŵƉŚĂƐŝnjĞƐƚŚĞƐƚƌĞŶŐƚŚŽĨŽƵƌƐƚƵĚLJĚĞƐŝŐŶ͘tĞƐƚƌŽŶŐůLJďĞůŝĞǀĞƚŚĂƚƚŚĞƐĞϱŐĞŶĞƐĂƌĞ ƉƌŽŵŝƐŝŶŐWŐĞŶĞƐĂŶĚĞŶĐŽƵƌĂŐĞƚŚĞWƌĞƐĞĂƌĐŚĮĞůĚƚŽƉĞƌĨŽƌŵĂĚĚŝƟŽŶĂůǀĂƌŝĂŶƚ ƐĐƌĞĞŶŝŶŐĂŶĚĨƵŶĐƟŽŶĂůǀĂůŝĚĂƟŽŶƐƚƵĚŝĞƐƚŽĐŽŶĮƌŵƚŚĞŝƌƉĂƚŚŽŐĞŶŝĐĐŽŶƚƌŝďƵƟŽŶƚŽ PD.

/^h^^/KEE&hdhZWZ^Wd/s^

ZĂƌĞǀĂƌŝĂŶƚĂŐŐƌĞŐĂƟŽŶĂŶĂůLJƐĞƐ dŚĞŵĂŝŶŽďũĞĐƟǀĞŽĨƚŚŝƐƚŚĞƐŝƐǁĂƐƚŽĚĞƚĞƌŵŝŶĞƚŚĞĐŽŶƚƌŝďƵƟŽŶŽĨƌĂƌĞĐŽĚŝŶŐǀĂƌŝĂŶƚƐ ƚŽW͘ƐƚŚĞƚĞƌŵŝŵƉůŝĞƐ͕ƌĂƌĞǀĂƌŝĂŶƚƐĂƌĞŝŶĨƌĞƋƵĞŶƚŝŶƚŚĞŐĞŶĞƌĂůƉŽƉƵůĂƟŽŶĂŶĚůĂƌŐĞ ƐĂŵƉůĞƐŝnjĞƐĂƌĞƌĞƋƵŝƌĞĚƚŽƌĞĂĐŚƐƵĸĐŝĞŶƚƐƚĂƟƐƟĐĂůƉŽǁĞƌĨŽƌƐƚĂŶĚĂƌĚƐŝŶŐůĞͲǀĂƌŝĂŶƚ ĂƐƐŽĐŝĂƟŽŶƚĞƐƚƐ͘ĞƐŝĚĞƐƚŚĞŽƉƟŽŶƐƚŽƐƚƵĚLJƌĂƌĞǀĂƌŝĂŶƚƐŝŶĨĂŵŝůŝĞƐŽƌŝŶĐƌĞĂƐĞƐĂŵƉůĞ ƐŝnjĞƐƚŽƌĞĂĐŚƐƚĂƟƐƟĐĂůƉŽǁĞƌ͕ĂƚŚŝƌĚĂƉƉƌŽĂĐŚĂŐŐƌĞŐĂƚĞƐƌĂƌĞǀĂƌŝĂŶƚƐŝŶƉƌĞƐĞůĞĐƚĞĚ units (e.g. genes or biological pathways), followed by comparison of the aggregated ĨƌĞƋƵĞŶĐLJ ƐƚĂƟƐƟĐƐ ďĞƚǁĞĞŶ ĐĂƐĞƐ ĂŶĚ ĐŽŶƚƌŽůƐ͘12 _{This strategy has been of great}

7

ĂƐƉĞĐŝĮĞĚD&ƚŚƌĞƐŚŽůĚĂƌĞĐŽŶƐŝĚĞƌĞĚ͕ǁŚŝůĞƚŚĞĮƌƐƚĂƉƉƌŽĂĐŚĨŽƌĐĞƐƚŚĞƌĞŵŽǀĂůŽĨ ǀĂƌŝĂŶƚƐƚŚĂƚĂƌĞŶŽƚƉƌĞĚŝĐƚĞĚƚŽďĞĚĞůĞƚĞƌŝŽƵƐ͕ƚŚĞƌĞďLJƉŽƚĞŶƟĂůůLJĞdžĐůƵĚŝŶŐƚƌƵĞĐĂƵƐĂů variants. We applied both approaches in this thesis, adding the second strategy in the ůĂƐƚǀĂƌŝĂŶƚĂŐŐƌĞŐĂƟŽŶĂƐƐŽĐŝĂƟŽŶĐŚĂƉƚĞƌŽŶĐĞŝƚǁĂƐŝŶƚƌŽĚƵĐĞĚďLJ^<d͘^ŝŐŶŝĮĐĂŶƚ ƌĂƌĞǀĂƌŝĂŶƚĂƐƐŽĐŝĂƟŽŶƐŽĨŐĞŶĞͲƐĞƚƐǁĞƌĞǀĂůŝĚĂƚĞĚǁŝƚŚĂƐĞĐŽŶĚŝŶĚĞƉĞŶĚĞŶƚŐĞŶĞƟĐ ĚĂƚĂƐĞƚĨŽƌĐŚĂƉƚĞƌϰĂŶĚϱ͕ŝŶĚŝĐĂƟŶŐƚŚĂƚďŽƚŚƉĂƚŚŽŐĞŶŝĐǀĂƌŝĂŶƚƐĞůĞĐƟŽŶĂƉƉƌŽĂĐŚĞƐ ĐŽƵůĚďĞĂƉƉůŝĞĚƐƵĐĐĞƐƐĨƵůůLJ͘ƐƚŚĞŐĞŶĞƟĐĞƟŽůŽŐLJŽĨĂĚŝƐĞĂƐĞŝƐĂƉƌŝŽƌŝƵŶŬŶŽǁŶŝƚŝƐ ƉƌĞĨĞƌĂďůĞƚŽƵƐĞďŽƚŚĨƵŶĐƟŽŶĂůǀĂƌŝĂŶƚƐĞůĞĐƟŽŶƐƚƌĂƚĞŐŝĞƐ͘ &ŝŶĚŝŶŐĂƐŝŐŶŝĮĐĂŶƚŐĞŶĞŽƌŐĞŶĞͲƐĞƚĂƐƐŽĐŝĂƟŽŶŝƐĞŶĐŽƵƌĂŐŝŶŐ͘,ŽǁĞǀĞƌ͕ĂƉĂƌƚ ĨƌŽŵŝŶĚŝĐĂƟŶŐƚŚĂƚƚŚĞŐĞŶĞ;ͲƐĞƚͿŝƐƉŽƚĞŶƟĂůůLJŝŶǀŽůǀĞĚŝŶWƉĂƚŚŽŐĞŶĞƐŝƐ͕ƚŚĞƐŝŐŶĂů ŝƐŶŽƚŝŶĨŽƌŵĂƟǀĞŽŶƚŚĞĞdžĂĐƚƌŽƵƚĞƚŚƌŽƵŐŚǁŚŝĐŚƚŚĞĂƐƐŽĐŝĂƟŽŶŽĐĐƵƌƐ͘dŚĞƌĞƐƵůƚƐ ŐĞŶĞƌĂƚĞĚďLJǀĂƌŝĂŶƚĂŐŐƌĞŐĂƟŽŶƚŽŽůƐ͕ƐƵĐŚĂƐ^<d14_{͕ůĂĐŬĂŶLJƌĞƉŽƌƚƐŽŶƐƉĞĐŝĮĐǀĂƌŝĂŶƚƐ͕} ƚŚĞƌĞĨŽƌĞƌĂƌĞĐĂƵƐĂůǀĂƌŝĂŶƚƐĂƌĞŶŽƚƉŝŶƉŽŝŶƚĞĚ͘&ƵƌƚŚĞƌŵŽƌĞ͕^<dƚĞƐƚƐĨŽƌĂƚǁŽͲƐŝĚĞĚ ŵŽĚĞůĂŶĚƚŚĞƌĞĨŽƌĞŚĂƐƚŚĞĚŝƐĂĚǀĂŶƚĂŐĞƚŚĂƚƚŚĞĚŝƌĞĐƟŽŶĂůŝƚLJŽĨƚŚĞĂŐŐƌĞŐĂƚĞĚĞīĞĐƚ ŝƐƵŶĚĞĮŶĞĚ͕ŵĞĂŶŝŶŐŝƚĐŽƵůĚďĞĞŝƚŚĞƌƉƌŽƚĞĐƟǀĞŽƌĚĂŵĂŐŝŶŐ͘,ŽǁĞǀĞƌ͕ĚĞĮŶŝŶŐƚŚĞ ĐĂƵƐĂůǀĂƌŝĂŶƚƐŝƐĞƐƐĞŶƟĂůĨŽƌŝŵƉƌŽǀĞĚŬŶŽǁůĞĚŐĞŽŶƵŶĚĞƌůLJŝŶŐŵŽůĞĐƵůĂƌƉƌŽĐĞƐƐĞƐ ĂŶĚ ĨŽůůŽǁͲƵƉ ĨƵŶĐƟŽŶĂů ĞdžƉĞƌŝŵĞŶƚƐ͘ dŚĞƌĞĨŽƌĞ͕ ŵĞƚŚŽĚƐ ƚŚĂƚ ŝĚĞŶƟĨLJ ŝŶĚŝǀŝĚƵĂů ĐĂƵƐĂů ǀĂƌŝĂŶƚƐ ĂŵŽŶŐ ƚŚĞ ĂŐŐƌĞŐĂƚĞĚ ƌĂƌĞ ǀĂƌŝĂŶƚ ĂƐƐŽĐŝĂƟŽŶ ĂƌĞ ƌĞƋƵŝƌĞĚ͘ dǁŽ ƐƵĐŚ ŵĞƚŚŽĚƐŚĂǀĞďĞĞŶƉƌŽƉŽƐĞĚ͕ŽĨǁŚŝĐŚƚŚĞĮƌƐƚŽŶĞĐŚŽŽƐĞƐĐĂƵƐĂůƌĂƌĞǀĂƌŝĂŶƚƐďĂƐĞĚ ŽŶďĂĐŬǁĂƌĚƐĞůŝŵŝŶĂƟŽŶ;Ϳ͘15_{sĂƌŝĂŶƚƐĂƌĞĚĞĮŶĞĚĂƐŶŽŶͲĐĂƵƐĂůŝĨƚŚĞŽǀĞƌĂůůŐĞŶĞ} ĂƐƐŽĐŝĂƟŽŶďĞĐŽŵĞƐƐƚƌŽŶŐĞƌĂŌĞƌĞdžĐůƵƐŝŽŶŽĨƚŚĞƐĞǀĂƌŝĂŶƚƐ͕ǁŚŝĐŚŝƐƉĞƌĨŽƌŵĞĚŽŶĂ ŽŶĞďLJŽŶĞďĂƐŝƐ͘dŚĞƐĞĐŽŶĚŵĞƚŚŽĚ͕ĐĂůůĞĚĂĚĂƉƟǀĞĐŽŵďŝŶĂƟŽŶŽĨP-values method (ADA)16_{͕ƉĞƌĨŽƌŵƐĂƐŝŵŝůĂƌƌĂƌĞǀĂƌŝĂŶƚĂŐŐƌĞŐĂƟŽŶƚĞƐƚůŝŬĞ^<dďƵƚŝƐďƵŝůƚƵƉŽŶƐŝŶŐůĞͲ}

marker p-values, therefore allowing to simultaneously perform an aggregated variant test ĂŶĚƉŝŶƉŽŝŶƟŶŐƚŚĞĐĂƵƐĂůǀĂƌŝĂŶƚƐ͘dŚŝƐůĂƩĞƌƐƚƌĂƚĞŐLJĞůŝŵŝŶĂƚĞƐŝŶĚŝǀŝĚƵĂůǀĂƌŝĂŶƚƐǁŝƚŚ higher pͲǀĂůƵĞƐĚƵƌŝŶŐƚŚĞĂƐƐŽĐŝĂƟŽŶƚĞƐƚƐ͕ǁŚŝĐŚĐŽƵůĚďĞŵŽƌĞƉŽǁĞƌĨƵůŝŶĐŽŵƉĂƌŝƐŽŶ ƚŽ^<dƚŚĂƚŝŶĐůƵĚĞƐĂůůǀĂƌŝĂŶƚƐƌĞŐĂƌĚůĞƐƐƚŚĞŝŶĚŝǀŝĚƵĂůǀĂƌŝĂŶƚƐŝŐŶŝĮĐĂŶĐĞůĞǀĞůƐ͘

7

allows the inclusion of only one covariate. Bearing in mind the heterogeneous state of our t^ĚĂƚĂ;ǁŚŝĐŚǁŝůůďĞĚŝƐĐƵƐƐĞĚŝŶƚŚĞŶĞdžƚƉĂƌĂŐƌĂƉŚͿ͕ƚŚŝƐǁŽƵůĚƐĞĞŵĂƐŝŵƉůŝƐƟĐ ŵŽĚĞůƌĞƐƵůƟŶŐŝŶƉŽƚĞŶƟĂůƉƌŝŽƌŝƟnjĂƟŽŶŽĨĂƐƐŽĐŝĂƟŽŶƐƚŚĂƚĂƌĞĚƌŝǀĞŶďLJĐŽŶĨŽƵŶĚŝŶŐ ĨĂĐƚŽƌƐ͘,ŽǁĞǀĞƌ͕ƚŚĞƚǁŽĚŝƐĐƵƐƐĞĚŵĞƚŚŽĚƐƚŚĂƚĂŝŵƚŽƐƵƌƉĂƐƐƚŚĞŝĚĞŶƟĮĐĂƟŽŶŽĨĂŶ ŽǀĞƌĂůůŐĞŶĞͲďĂƐĞĚĂƐƐŽĐŝĂƟŽŶďLJĂĚĚŝƟŽŶĂůůLJĞƐƚĂďůŝƐŚŝŶŐƚŚĞƚƌƵĞĐĂƵƐĂůǀĂƌŝĂŶƚƐ͕ĂƌĞ ǀĂůƵĂďůĞŝŶŝƟĂƟǀĞƐƚŽĚĞĂůǁŝƚŚƚŚĞĐŚĂůůĞŶŐĞƚŽŝŶƚĞƌƉƌĞƚƚŚĞũŽŝŶƚĂƐƐŽĐŝĂƟŽŶƌĞƐƵůƚƐ͘ ƵŝůĚŝŶŐĨƵƌƚŚĞƌŽŶƚŚĞƐĞĐŽŶĐĞƉƚƐǁŝůůůŝŬĞůLJŝŵƉƌŽǀĞƚŚĞĐƵƌƌĞŶƚƌĂƌĞǀĂƌŝĂŶƚĂŐŐƌĞŐĂƟŽŶ ďŝŽŝŶĨŽƌŵĂƟĐƐƚŽŽůƐ͘  ůĂƐƚ ĐŽŶĐĞƌŶ ƌĞŐĂƌĚŝŶŐ ƌĂƌĞ ǀĂƌŝĂŶƚ ĂƐƐŽĐŝĂƟŽŶ ƐƚƵĚŝĞƐ ĞŶĐŽŵƉĂƐƐĞƐ ƚŚĞ ŝŶŇƵĞŶĐĞŽĨĐŽŶĨŽƵŶĚŝŶŐĨĂĐƚŽƌƐ͘'t^͕ƚĞƐƟŶŐƚŚĞĂƐƐŽĐŝĂƟŽŶŽĨĐŽŵŵŽŶǀĂƌŝĂŶƚƐ͕ĂƌĞ ƉƌŽŶĞƚŽƉŽƉƵůĂƟŽŶĚŝīĞƌĞŶĐĞƐĂŶĚƚŚĞŐŽůĚƐƚĂŶĚĂƌĚŝƐƚŽĐŽƌƌĞĐƚĨŽƌƉŽƚĞŶƟĂůƉŽƉƵůĂƟŽŶ ƐƚƌĂƟĮĐĂƟŽŶďLJƚŚĞŝŶĐůƵƐŝŽŶŽĨƉƌŝŶĐŝƉůĞĐŽŵƉŽŶĞŶƚƐ͘17_{ZĂƌĞǀĂƌŝĂŶƚĂƐƐŽĐŝĂƟŽŶƐƚƵĚŝĞƐ} ĂƌĞ ĞǀĞŶ ŵŽƌĞ ƐĞŶƐŝƟǀĞ ƚŽ ĐŽŶĨŽƵŶĚŝŶŐ ĨĂĐƚŽƌƐ͘ DŽƌĞ ƐƵďƚůĞ ƐLJƐƚĞŵĂƟĐ ĂŶĐĞƐƚƌLJ ĚŝīĞƌĞŶĐĞƐĐŽƵůĚƌĞƐƵůƚŝŶƐƉƵƌŝŽƵƐŽƵƚĐŽŵĞƐĂŶĚĚŝīĞƌĞŶĐĞƐŝŶůŝďƌĂƌLJĐĂƉƚƵƌĞŬŝƚƐĂƌĞ ĂĐŽŶĐĞƌŶ͘ZĂƌĞǀĂƌŝĂŶƚƐƚĞŶĚƚŽďĞŵŽƌĞƉŽƉƵůĂƟŽŶƐƉĞĐŝĮĐƚŚĂŶĐŽŵŵŽŶǀĂƌŝĂƟŽŶ͘18,19 KŶĞ ĐŽŶǀŝŶĐŝŶŐ ƐƚƵĚLJ ƐŚŽǁĞĚ ĞůĞǀĂƚĞĚ ƌĂƚĞƐ ŽĨ ƐƉƵƌŝŽƵƐ ŽƵƚĐŽŵĞƐ ĨŽƌ ϵ ƌĂƌĞ ǀĂƌŝĂŶƚ ĂƐƐŽĐŝĂƟŽŶŵĞƚŚŽĚƐĂƐĂƌĞƐƵůƚŽĨĮŶĞͲƐĐĂůĞƉŽƉƵůĂƟŽŶƐƚƌƵĐƚƵƌĞ͘20 _{A small country with}

7

dŚĞƐĞǀĂƌŝĂŶƚƐǁĞƌĞŶŽƚƉƌĞƐĞŶƚǁŝƚŚŝŶƚŚĞ/W't^ĚĂƚĂƐĞƚ͘tĞĚŝĚĮŶĚϯŽƚŚĞƌƌĂƌĞ variants in CHCHD2, all present in cases and not a single coding variant in controls, implying ƚŚĂƚƚŚŝƐŵŝŐŚƚďĞĂƌĂƌĞŐĞŶĞƟĐƌŝƐŬĨĂĐƚŽƌĨŽƌƚŚĞƵƌŽƉĞĂŶƉŽƉƵůĂƟŽŶƚŽŽ͘džƉůŽƌŝŶŐ ŽƚŚĞƌƉŽƉƵůĂƟŽŶƐ;ƐŝĂŶǀƐ͘ƵƌŽƉĞĂŶͿĐŽŵƉůŝĐĂƚĞƐƌĞƉůŝĐĂƟŽŶĂƐƌĂƌĞǀĂƌŝĂŶƚƐĂƌĞŽŌĞŶ ƉŽƉƵůĂƟŽŶƐƉĞĐŝĮĐ͘ŚĂƉƚĞƌϮƐŚŽǁƐƚŚĂƚǁŝƚŚŽŶůLJϯŝĚĞŶƟĮĞĚǀĂƌŝĂŶƚƐŝƚŝƐŝŵƉŽƐƐŝďůĞƚŽ replicate CHCHD2 ďLJƌĂƌĞǀĂƌŝĂŶƚĂŐŐƌĞŐĂƟŽŶƚĞƐƚĂƐƚŚĞǀĂƌŝĂŶƚĨƌĞƋƵĞŶĐŝĞƐĂƌĞƚŽŽůŽǁ ƚŽƌĞĂĐŚƐŝŐŶŝĮĐĂŶĐĞ͘KǀĞƌĂůů͕ƌĞƉůŝĐĂƟŽŶŽĨƌĂƌĞǀĂƌŝĂŶƚƐƌĞƋƵŝƌĞƐůĂƌŐĞĚĂƚĂƐĞƚƐǁŚŝĐŚŝƐ ŽŌĞŶŝŶĂƉƉůŝĐĂďůĞĚƵĞƚŽŝŶƐƵĸĐŝĞŶƚŶƵŵďĞƌƐŽĨƉĂƟĞŶƚƐŽƌĮŶĂŶĐŝĂůƌĞƐŽƵƌĐĞƐ͘ ĞƐŝĚĞƐƚŚĞƌĞƉůŝĐĂƟŽŶŽĨĂŐĞŶĞƚŚĂƚǁĂƐĚŝƐĐŽǀĞƌĞĚďLJĂŶŽƚŚĞƌƌĞƐĞĂƌĐŚŐƌŽƵƉ ŝŶĐŚĂƉƚĞƌϮ͕ǁĞĞdžƉĞƌŝĞŶĐĞĚĐŽŵƉĂƌĂďůĞƌĞƉůŝĐĂƟŽŶŽďƐƚĂĐůĞƐĨŽƌŽƵƌŝŶͲŚŽƵƐĞĞdžƉůŽƌĂƟǀĞ ĂŶĂůLJƐĞƐ͘ƐǁĞǁĞƌĞůĂĐŬŝŶŐĂƐĞĐŽŶĚŝŶĚĞƉĞŶĚĞŶƚt^ĚĂƚĂƐĞƚƐŝŵŝůĂƌƚŽƚŚĞƐŝnjĞŽĨƚŚĞ ŽƌŝŐŝŶĂůŽŶĞ;Εϭ͕ϮϬϬĐĂƐĞƐĂŶĚΕϭ͕ϳϬϬĐŽŶƚƌŽůƐͿ͕ǁĞĂƩĞŵƉƚĞĚƚŽƌĞƉůŝĐĂƚĞŽƵƌĮŶĚŝŶŐƐ ǁŝƚŚĂǀĂƌŝĞƚLJŽĨŽƚŚĞƌŐĞŶĞƟĐĞdžŽŵĞĚĂƚĂƐĞƚƐ͘/ŶĐŚĂƉƚĞƌϯ͕ǁŚĞƌĞǁĞĞƐƚĂďůŝƐŚĞĚƚŚĞƌŽůĞ of rare variants in common PD risk loci, we used the NeuroX dataset as a second dataset. ƐƚŚĞEĞƵƌŽyĂƌƌĂLJĐŽŶƚĂŝŶƐĂĐƵƐƚŽŵͲĂƌƌĂLJ͕ŝƚǁĂƐĞŶƌŝĐŚĞĚĨŽƌǀĂƌŝĂŶƚƐŝŶW't^ůŽĐŝ͘ ,ŽǁĞǀĞƌ͕ŶŽŐĞŶĞƟĐƌĞƉůŝĐĂƟŽŶǁĂƐŽďƐĞƌǀĞĚ͘&ŽƌĐŚĂƉƚĞƌϰ͕ĨŽĐƵƐŝŶŐŽŶƚŚĞĞīĞĐƚŽĨ rare variants in LSD genes, we were more successful. By using a small second independent t^ĚĂƚĂƐĞƚŽĨƚŚĞƉƵďůŝĐĂǀĂŝůĂďůĞWWD/ƉƌŽũĞĐƚ;ĂƉƉƌŽdžŝŵĂƚĞůLJϭͬϱth_{ŝŶƐŝnjĞͿ͕}26 _{we were}

ĂďůĞ ƚŽ ƌĞƉůŝĐĂƚĞ ƚŚĞ ũŽŝŶƚ ĞīĞĐƚ ŽĨ ƌĂƌĞ ĚĞůĞƚĞƌŝŽƵƐ ǀĂƌŝĂŶƚƐ ǁŚĞŶ ĐŽŶƐŝĚĞƌŝŶŐ Ăůů >^ ŐĞŶĞƐƐŝŵƵůƚĂŶĞŽƵƐůLJ͘ŶĚĞǀĞŶƚŚŽƵŐŚƚŚĞEĞƵƌŽyĂƌƌĂLJǁĂƐŶŽƚƐƉĞĐŝĮĐĂůůLJĞŶƌŝĐŚĞĚ for variants with LSD genes, we also replicated an aggregated rare variant signal for the ƚŽƚĂůŐĞŶĞͲƐĞƚŝŶEĞƵƌŽy͘EĞƵƌŽyŚĂƐƚŚĞĂĚǀĂŶƚĂŐĞƚŽĐŽŶƐŝƐƚŽĨĂƌĞůĂƟǀĞůĂƌŐĞƐĂŵƉůĞ ƐŝnjĞ;ĂůŵŽƐƚϳ͕ϬϬϬĐĂƐĞƐĂŶĚϲ͕ϬϬϬĐŽŶƚƌŽůƐͿ͕ƚŚĞƌĞĨŽƌĞƐƟŶŐƉŽǁĞƌ͘tŚĞŶĞƐƚĂďůŝƐŚŝŶŐ ƚŚĞĂŐŐƌĞŐĂƚĞĚĞīĞĐƚŽĨĐŽĚŝŶŐǀĂƌŝĂŶƚƐŝŶƚƌĂŶƐĐƌŝƉƚŽŵŝĐƐͲďĂƐĞĚĚĞƌĞŐƵůĂƚĞĚƉĂƚŚǁĂLJƐ ŝŶĐŚĂƉƚĞƌϱ͕ǁĞĂŝŵĞĚƚŽƌĞƉůŝĐĂƚĞŽƵƌĮŶĚŝŶŐƐǁŝƚŚĂůĂƌŐĞƌt^ĚĂƚĂƐĞƚĂƐǁĞŝŶƚŚĞ ŵĞĂŶƟŵĞŽďƚĂŝŶĞĚĂĐĐĞƐƐƚŽΕϭ͕ϬϬϬĂĚĚŝƟŽŶĂůWĞdžŽŵĞƐƚŚƌŽƵŐŚĂŶŽǀĞůĐŽůůĂďŽƌĂƟŽŶ͘ LJŵĞƚĂͲĂŶĂůLJnjŝŶŐƚŚŝƐŶŽǀĞůĚĂƚĂƐĞƚǁŝƚŚƚŚĞWWD/ĚĂƚĂƐĞƚǁĞǁĞƌĞĂďůĞƚŽŐĞŶĞƌĂƚĞ Ă ůĂƌŐĞƌ ƌĞƉůŝĐĂƟŽŶ ĚĂƚĂƐĞƚ͘ dŚƵƐ͕ ǁĞ ŵĂŶĂŐĞĚ ƚŽ ĚĞĂů ǁŝƚŚ ƚŚĞ ƐĂŵƉůĞ ƐŝnjĞ ƌĞůĂƚĞĚ ƌĞƉůŝĐĂƟŽŶŝƐƐƵĞƐĨŽƌĂůůŽƵƌĂŶĂůLJƐĞƐ͘

7

dŚĞĐƵƌƌĞŶƚƌĞƉůŝĐĂƟŽŶĐŚĂůůĞŶŐĞƐŽĨƌĂƌĞǀĂƌŝĂŶƚĂƐƐŽĐŝĂƟŽŶƐŝŐŶĂůƐ͕ĞŵƉŚĂƐŝnjĞƐ the need for researchers to collaborate. When joining forces (funding resources and subject cohorts) it possibly increases the number of cases to ten thousands of ŝŶĚŝǀŝĚƵĂůƐ͘dŚĞ/W'ŝƐĂŶĞdžĐĞůůĞŶƚƐƚĂƌƚďƵƚĞǀĞŶůĂƌŐĞƌŝŶŝƟĂƟǀĞƐĂƌĞƌĞƋƵŝƌĞĚ͘/ĚĞĂůůLJ͕ all generated sequencing data would be publically shared on repositories, such as the ĚĂƚĂďĂƐĞ ŽĨ 'ĞŶŽƚLJƉĞƐ ĂŶĚ WŚĞŶŽƚLJƉĞƐ ;Ěď'ĂWͿ Žƌ ƚŚĞ ƵƌŽƉĞĂŶ 'ĞŶŽŵĞͲƉŚĞŶŽŵĞ ƌĐŚŝǀĞ;'Ϳ͘27,28_{/ƚƐĞĞŵƐƚŚĞŐĞŶĞƟĐǁŽƌůĚŝƐƐůŽǁůLJŵŽǀŝŶŐƚŽǁĂƌĚƐƚŚŝƐƐŝƚƵĂƟŽŶĂƐ} ŵĂŶLJƐĐŝĞŶƟĮĐũŽƵƌŶĂůƐĂƌĞƉƌŽŵŽƟŶŐĚĂƚĂƐŚĂƌŝŶŐďLJĚĞŵĂŶĚŝŶŐƚŚĞƉƵďůŝĐƌĞůĞĂƐĞŽĨ ƚŚĞĂŶĂůLJnjĞĚĚĂƚĂŝŶĂƌĞƉŽƐŝƚŽƌLJ͘ 'ĞŶĞͲƐĞƚĂŶĂůLJƐŝƐ ŚĂƉƚĞƌϯ͕ϰĂŶĚϱƉĞƌĨŽƌŵĞĚǀĂƌŝĂŶƚĂŐŐƌĞŐĂƟŽŶĂƐƐŽĐŝĂƟŽŶƚĞƐƚƐŝŶƉƌĞĚĞĮŶĞĚŐĞŶĞͲ ƐĞƚƐƚŚĂƚǁĞƌĞďĂƐĞĚŽŶďŝŽůŽŐŝĐĂůƉĂƚŚǁĂLJƐŽƌŽƚŚĞƌĚŝƐĞĂƐĞͲƌĞůĂƚĞĚƉƌŽƉĞƌƟĞƐ͘^ŝŵŝůĂƌůLJ ƚŽƚŚĞŝƐƐƵĞŽďƐĞƌǀĞĚŝŶƐŝŐŶŝĮĐĂŶƚŐĞŶĞͲďĂƐĞĚĂƐƐŽĐŝĂƟŽŶƌĞƐƵůƚƐ͕ǁŚĞƌĞŝƚŝƐŝŵƉŽƐƐŝďůĞ ƚŽ ĚŝƐƟŶŐƵŝƐŚ ŐĞŶƵŝŶĞ ĐĂƵƐĂů ǀĂƌŝĂŶƚƐ ĨƌŽŵ ƚŚĞ ďĞŶŝŐŶ ŽŶĞƐ͕ ŝƚ ŝƐ ĨŽƌ ƐŝŐŶŝĮĐĂŶƚ ŐĞŶĞͲ ƐĞƚĂƐƐŽĐŝĂƟŽŶƐĐŽŵƉůŝĐĂƚĞĚƚŽĂƐƐĞƐƐǁŚŝĐŚƐƉĞĐŝĮĐŐĞŶĞƐĂƌĞŐĞŶĞƌĂƟŶŐƚŚĞƐŝŐŶĂů͘ ƐĞĐŽŶĚĐŚĂůůĞŶŐĞ͕ǁŚŝĐŚŝƐƐƉĞĐŝĮĐƚŽƚŚĞŐĞŶĞͲƐĞƚĂƐƐŽĐŝĂƟŽŶĂŶĂůLJƐŝƐ͕ŝƐƚŚĞƐĞůĞĐƟŽŶŽĨ ĐŽƌƌĞĐƚƐĞƚƐŽĨŐĞŶĞƐƚŚĂƚĂƌĞĂƐƐŽĐŝĂƚĞĚƚŽW͘ƐǁĞŽďƐĞƌǀĞĚƐŝŐŶŝĮĐĂŶƚĂŶĚƌĞƉůŝĐĂďůĞ ŐĞŶĞͲƐĞƚĮŶĚŝŶŐƐĨŽƌƚŚĞ>^ŐĞŶĞͲƐĞƚŝŶĐŚĂƉƚĞƌϰ͕ĂŶĚƚŚĞŵŝƚŽĐŚŽŶĚƌŝĂůĚLJƐĨƵŶĐƟŽŶ and caveolar-mediated endocytosis gene-sets in chapter 5, we assume to have chosen a ƌĞůĂƟǀĞůLJĐůŽƐĞƌĞƉƌĞƐĞŶƚĂƟŽŶŽĨƚƌƵůLJĂƐƐŽĐŝĂƚĞĚƉĂƚŚǁĂLJƐ͘,ŽǁĞǀĞƌ͕ƚŚĞŐĞŶĞͲƐĞƚďĂƐĞĚ ŽŶƚŚĞƉƌĞǀŝŽƵƐůLJƉƵďůŝƐŚĞĚW't^ƌŝƐŬůŽĐŝŽĨĐŚĂƉƚĞƌϯŝƐŵŽƌĞĐŽŵƉůĞdž͘dŚĞƌĞŝƐŶŽ ƐŝŐŶŝĮĐĂŶƚũŽŝŶƚĞīĞĐƚŽĨƌĂƌĞǀĂƌŝĂŶƚƐĨŽƌƚŚŝƐŐĞŶĞͲƐĞƚ͕ďƵƚŝƚŝƐƐƟůůƵŶĚĞĐŝĚĞĚǁŚĞƚŚĞƌ rare variants within common PD risk loci are truly not associated to PD or that the gene-set is not including the true causal genes underneath the common loci.

ŚĂƉƚĞƌϯƐŚŽǁƐũƵƐƚŚŽǁĞƐƐĞŶƟĂůĐŽƌƌĞĐƚĚĞĮŶŝƟŽŶŽĨĂŐĞŶĞͲƐĞƚŝƐƚŽďĞĂďůĞ ƚŽĚƌĂǁĚĞĮŶŝƟǀĞĐŽŶĐůƵƐŝŽŶƐ͘^ƵďƐĞƋƵĞŶƚƚŽƚŚĞĞdžƚĞŶƐŝǀĞĂŶĂůLJƐĞƐŽĨƚŚŝƐĐŚĂƉƚĞƌ͕ǁĞ ĂƌĞĐƵƌƌĞŶƚůLJƐƟůůƵŶĂďůĞƚŽĂƌŐƵĞŝŶĨĂǀŽƌŽƌĂŐĂŝŶƐƚĂŐĞŶƵŝŶĞŝŶŇƵĞŶĐĞŽĨƌĂƌĞǀĂƌŝĂŶƚƐ in common PD risk loci. As discussed in the chapter 3, basing a gene-set on common risk ůŽĐŝŝƐĐŚĂůůĞŶŐŝŶŐĂƐŽŌĞŶŵƵůƟƉůĞŐĞŶĞƐĂƌĞůŽĐĂƚĞĚǁŝƚŚŝŶƌŝƐŬůŽĐŝ͕ĂůůĞƋƵĂůůLJůŝŬĞůLJ ĐĂŶĚŝĚĂƚĞƐƚŽďĞƚŚĞĐĂƵƐĂůŽŶĞƐ͘ůƚŚŽƵŐŚǁĞŚĂǀĞĂƩĞŵƉƚĞĚƚŽĞƐƚĂďůŝƐŚƚŚĞƚƌƵĞĐĂƵƐĂů ŐĞŶĞƐ ďĂƐĞĚ ŽŶ ƵŶĚĞƌůLJŝŶŐ ĨƵŶĐƟŽŶĂů ƐŝŵŝůĂƌŝƟĞƐ ďĞƚǁĞĞŶ ƚŚĞ ĚŝīĞƌĞŶƚ 't^ ƉĞĂŬƐ͕ there is a chance that non-causal genes were selected.

ĞƐŝĚĞƐƚŚĞĨĂĐƚƚŚĂƚƚŚŝƐƐŚŽǁƐƚŚĞŝŵƉŽƌƚĂŶĐĞŽĨĂĚĞƋƵĂƚĞŐĞŶĞͲƐĞƚƐĞůĞĐƟŽŶƐ͕ ŝƚĨƵƌƚŚĞƌŵŽƌĞĞŵƉŚĂƐŝnjĞƐƚŚĞŶĞĞĚĨŽƌŝŵƉƌŽǀĞĚŵĞƚŚŽĚƐƚŽĨƵŶĐƟŽŶĂůůLJŝŶƚĞƌƉƌĞƚ't^ ƌĞƐƵůƚƐ͘dŚĞWƌŝdž&ŝdžĞƚŽŽů29 _{that was used for this purpose in chapter 3 is an improvement}

7

ĨƵŶĐƟŽŶƐ͕ŵŝŐŚƚƌĞƐƵůƚŝŶĨĂůƐĞŶĞŐĂƟǀĞƐŝĨŵĂŶLJĚŝƐƟŶĐƚŵŽůĞĐƵůĂƌƉƌŽĐĞƐƐĞƐĂƌĞĂīĞĐƚĞĚ ŝŶ Ă ĚŝƐĞĂƐĞ ĞƟŽůŽŐLJ͘ &ƵƌƚŚĞƌŵŽƌĞ͕ Wƌŝdž&ŝdžĞ ŚĂƐ Ă ĚŝƐĞĂƐĞͲƵŶďŝĂƐĞĚ ĂƉƉƌŽĂĐŚ ŵĞĂŶŝŶŐ it will not consider disease-related features. Yet it might be helpful to build underlying ĨƵŶĐƟŽŶĂů ŶĞƚǁŽƌŬƐ ŽŶ ĨŽƌ ĞdžĂŵƉůĞ ƚƌĂŶƐĐƌŝƉƚŽŵŝĐƐ ĚĂƚĂƐĞƚƐ ŽĨ ďŽĚLJ ƟƐƐƵĞƐ ƚŚĂƚ ĂƌĞ ĂīĞĐƚĞĚŝŶƚŚĞĚŝƐĞĂƐĞƉĂƚŚŽŐĞŶĞƐŝƐ͘>ĂƐƚůLJ͕ŽŶĞƐŚŽƵůĚĐŽŶƐŝĚĞƌƚŚĞƉŽƐƐŝďŝůŝƚLJƚŚĂƚĂŶ associated locus (represented by a linkage disequilibrium (LD) block) harbors the causal ǀĂƌŝĂŶƚŝŶĂƌĞŐƵůĂƚŽƌLJĞůĞŵĞŶƚ;Ğ͘Ő͘ĂŶĞŶŚĂŶĐĞƌͿǁŚŝĐŚŝŶŇƵĞŶĐĞƐƚŚĞĞdžƉƌĞƐƐŝŽŶŽĨĂ gene beyond the borders of the LD block. eQTL analysis is able to detect such signals.30

dŚĞĚĞǀĞůŽƉŵĞŶƚŽĨĂďŝŽŝŶĨŽƌŵĂƟĐƐƚŽŽůƚŚĂƚƌĞĚƵĐĞƐƚŚĞŶƵŵďĞƌŽĨĐĂŶĚŝĚĂƚĞŐĞŶĞƐ ƉĞƌ ůŽĐƵƐ ďLJ ŝŶƚĞŐƌĂƟŽŶ ŽĨ ƚŚĞƐĞ ĂƐƉĞĐƚƐ ǁŽƵůĚ ďĞ ĂŶ ŝŶƐƚƌƵĐƟǀĞ ŐƵŝĚĞ ĨŽƌ ĨƵŶĐƟŽŶĂů ĨŽůůŽǁͲƵƉĞdžƉĞƌŝŵĞŶƚƐĂŝŵŝŶŐƚŽǀĂůŝĚĂƚĞƚŚĞƉĂƚŚŽŐĞŶŝĐĞīĞĐƚƐŽĨƚŚĞƐĞůĞĐƚĞĚŐĞŶĞƐŽŶ the disease of interest.

 ĮŶĂů ƉŽŝŶƚ ĨŽƌ ŝŵƉƌŽǀĞŵĞŶƚ ĨŽƌ ŐĞŶĞͲƐĞƚ ĂƐƐŽĐŝĂƟŽŶ ĂŶĂůLJƐŝƐ ŝŶĐůƵĚĞƐ ƚŚĞ ĚĞǀĞůŽƉŵĞŶƚ ŽĨ ŐĞŶĞͲƐĞƚ ǀĂƌŝĂŶƚ ĂŐŐƌĞŐĂƟŽŶ ƚŽŽůƐ ƚŚĂƚ ĂƌĞ ƐƉĞĐŝĮĐ ĨŽƌ ƌĂƌĞ ǀĂƌŝĂŶƚƐ͘ DƵůƟƉůĞŐĞŶĞͲƐĞƚƐŽŌǁĂƌĞƉĂĐŬĂŐĞƐĞdžŝƐƚƚŚĂƚĂƌĞĚĞƐŝŐŶĞĚƚŽƚĞƐƚĨŽƌŐĞŶĞͲƐĞƚĂƐƐŽĐŝĂƟŽŶ by using common variants generated with genotype arrays.31 _{A commonly used}

7

within the research covered by this thesis puts emphasis on the molecular processes involved in mitochondrial health (chapter 2, 5 and 6), lysosomal storage (chapter 4 and 6), caveolar-mediated endocytosis (chapter 5) and renin-angiotensin signaling (chapter ϱͿ͘dĂƌŐĞƟŶŐƚŚĞƐĞĚĞƌĞŐƵůĂƚĞĚƉĂƚŚǁĂLJƐǁŝƚŚĚƌƵŐƐŵŝŐŚƚďĞĐŽŵĞĂĨƌƵŝƞƵůĂƉƉƌŽĂĐŚƚŽ ƚƌĞĂƚW͘ƐƉĞĐŝĂůůLJĐŽŶƐŝĚĞƌŝŶŐƚŚĞŚĞƚĞƌŽŐĞŶĞŽƵƐĞƟŽůŽŐLJŽĨƚŚĞĚŝƐĞĂƐĞ͕ǁŚŝĐŚƐƵŐŐĞƐƚƐ ƚŚĂƚĂĨŽĐƵƐŽŶĐŽŶǀĞƌŐŝŶŐĚĞƌĞŐƵůĂƚĞĚƉĂƚŚǁĂLJƐĐŽƵůĚďĞďĞŶĞĮĐŝĂůĨŽƌĂůĂƌŐĞƌŐƌŽƵƉŽĨ WƉĂƟĞŶƚƐ͘ dŚĞƐƚƌĂƚĞŐLJƚŽǀŝĞǁĚŝƐĞĂƐĞƐĂƐŚĞĂůƚŚĐŽŶĚŝƟŽŶƐǁŚĞƌĞŵŽůĞĐƵůĂƌƉƌŽĐĞƐƐĞƐ ĂƌĞ ĚĞƌĞŐƵůĂƚĞĚ͕ ƚŚĞƌĞďLJ ĂīĞĐƟŶŐ ŵƵůƟƉůĞ ůĞǀĞůƐ ŽĨ ĨƵŶĐƟŽŶĂů ƵŶŝƚƐ͕ ŝƐ Ă ƚŚĞŽƌLJ ƚŚĂƚ is gaining popularity.33_{ dŚŝƐ ƐLJƐƚĞŵͲďĂƐĞĚ ĂƉƉƌŽĂĐŚ ƌĞůŝĞƐ ĨŽƌ Ă ůĂƌŐĞ ƉĂƌƚ ŽŶ ŐĞŶĞƟĐ}

studies, showing the importance to perform WES research such as ours. However, cellular ƉƌŽĐĞƐƐĞƐĂƌĞĚLJŶĂŵŝĐ͕ƚĞŵƉŽƌĂƌLJĂŶĚŝŶƚĞƌĂĐƟǀĞ͕ƚŚĞƌĞďLJŵĂŬŝŶŐƚŚĞŵĐŽŵƉůĞdž͘dŚĞLJ ĐŽŶƐƟƚƵƚĞŵƵůƟƉůĞůĞǀĞůƐŽĨĨƵŶĐƟŽŶĂůŶĞƚǁŽƌŬƐǁŚŝĐŚĂƌĞŝŶƚĞƌĐŽŶŶĞĐƚĞĚ͘/ƚŝƐƚŚĞƌĞĨŽƌĞ ƉƌĞĨĞƌĂďůĞƚŽƐƚƵĚLJŐĞŶĞƟĐƐǁŚŝůĞƉƵƫŶŐŝƚŝŶƉĞƌƐƉĞĐƟǀĞŽĨŐĞŶĞĞdžƉƌĞƐƐŝŽŶ͕ƉƌŽƚĞŝŶ ƐLJŶƚŚĞƐŝƐ Žƌ ĞŶĞƌŐLJ ĐŽŶƐƵŵƉƟŽŶ͘ dŚĞ ƐLJƐƚĞŵͲďĂƐĞĚ ĂƉƉƌŽĂĐŚ ƚŚĞƌĞĨŽƌĞ ĞŶĐŽŵƉĂƐƐĞƐ ŵƵůƟƉůĞůĞǀĞůƐŽĨďŝŽůŽŐLJƐLJƐƚĞŵƐ͕ƌĞƉƌĞƐĞŶƚĞĚďLJƚŚĞĚŝīĞƌĞŶƚůĞǀĞůƐŽĨŽŵŝĐƐĚĂƚĂ͕ǁŚŝĐŚ ƐŚŽƵůĚďĞǀŝĞǁĞĚĂƐŝŶƚĞƌƚǁŝŶĞĚƐƵďũĞĐƚƐƌĂƚŚĞƌƚŚĂŶĂĚĚƌĞƐƐŝŶŐƚŚĞŵĂƐĚŝƐƟŶĐƚƚŽƉŝĐƐ͘ ŶĞdžĐĞƉƟŽŶĂůƐƚƵĚLJŽŶŐĞŶĞƟĐĨĂĐƚŽƌƐŽĨŚĞƌĞĚŝƚĂƌLJƐƉĂƐƟĐƉĂƌĂƉůĞŐŝĂƐ;,^WͿ͕ĂŵŽƚŽƌ ŶĞƵƌŽŶĚŝƐĞĂƐĞ͕ƐĞƌǀĞƐĂƐĂŐŽŽĚĞdžĂŵƉůĞŽŶŽŵŝĐƐŝŶƚĞŐƌĂƟŽŶůĞĂĚŝŶŐƚŽŵŽƌĞŝŶͲĚĞƉƚŚ ŐĞŶĞƟĐĮŶĚŝŶŐƐ͘34_{ĂƐĞĚŽŶƉƵďůŝĐĂůůLJĂǀĂŝůĂďůĞƉƌŽƚĞŝŶŝŶƚĞƌĂĐƟŽŶĚĂƚĂƚŚĞLJŐĞŶĞƌĂƚĞĚ}

a proteome network of proteins and genes that interact with known HSP genes. This ͚,^WŽŵĞ͛ ǁĂƐ ƚŚĞŝƌ ŐƵŝĚĞ ƚŽ ŝŶǀĞƐƟŐĂƚĞ Ă t^ ĚĂƚĂƐĞƚ ĐŽŶƐŝƐƟŶŐ ŽĨ ϱϱ ĨĂŵŝůŝĞƐ ǁŝƚŚ ĂƵƚŽƐŽŵĂůƌĞĐĞƐƐŝǀĞ,^WĂŶĚƌĞƐƵůƚĞĚŝŶƚŚĞŝĚĞŶƟĮĐĂƟŽŶŽĨϭϴŶŽǀĞůŐĞŶĞƟĐĨĂĐƚŽƌƐ͘ dŚĞƌĞĨŽƌĞ͕ƚŚĞĐŽŵďŝŶĂƟŽŶŽĨĚŝīĞƌĞŶƚŽŵŝĐƐůĞǀĞůƐŝƐĂĨƌƵŝƞƵůĂƉƉƌŽĂĐŚ͕ŝŶĐůƵĚŝŶŐƚŚĞ ŝŶƚĞŐƌĂƟŽŶŽĨŝŶͲŚŽƵƐĞŽŵŝĐƐĚĂƚĂƐĞƚĂƐǁĞůůĂƐƉƵďůŝĐĚĂƚĂƐĞƚƐ͕ƐƵĐŚĂƐEK35 _and &EdKD36_. /ŶĐŚĂƉƚĞƌϱǁĞŚĂǀĞĐŽŶŶĞĐƚĞĚƚƌĂŶƐĐƌŝƉƚŽŵŝĐƐǁŝƚŚŐĞŶŽŵŝĐƐĚĂƚĂďLJƚĞƐƟŶŐ ƚŚĞŐĞŶĞƟĐŝŶǀŽůǀĞŵĞŶƚŽĨďŝŽůŽŐŝĐĂůƉĂƚŚǁĂLJƐƚŚĂƚǁĞƌĞƉƌĞǀŝŽƵƐůLJĚĞƚĞƌŵŝŶĞĚƚŚƌŽƵŐŚ ŐĞŶĞͲĞdžƉƌĞƐƐŝŽŶ ƉƌŽĮůŝŶŐ ƌĞƐĞĂƌĐŚ͘ ^ŝŵŝůĂƌůLJ͕ ŝŶ ĐŚĂƉƚĞƌ ϲ ǁĞ ƵƐĞĚ ƉƵďůŝĐĂůůLJ ĂǀĂŝůĂďůĞ ƌĞƐŽƵƌĐĞƐ ĂŶĚ h< ĂŶĂůLJƐĞƐĐŽǀĞƌŝŶŐŐĞŶĞ;ĐŽͲͿĞdžƉƌĞƐƐŝŽŶ ŽƵƚĐŽŵĞƐƚŽ ĨƵŶĐƟŽŶĂůůLJ ŝŶƚĞƌƉƌĞƚ ŽƵƌ ŐĞŶĞƟĐ ƌĞƐƵůƚƐ͘ dŚĞƐĞ ƚǁŽ ƐƚƵĚŝĞƐ ƵƟůŝnjĞ ĚŝīĞƌĞŶƚ ŽŵŝĐƐ ĚĂƚĂ ůĞǀĞůƐ ŝŶ Ă ĐŽŵƉůĞŵĞŶƚĂƌLJ ĨĂƐŚŝŽŶ͘ ǀŝĚĞŶĐĞ ŽƌŝŐŝŶĂƟŶŐ ĨƌŽŵ ĚŝīĞƌĞŶƚ ĨƵŶĐƟŽŶĂů ůĞǀĞůƐ ŝŶĐƌĞĂƐĞƐ ƚŚĞůŝŬĞůŝŚŽŽĚŽĨŝĚĞŶƟĨLJŝŶŐĂŐĞŶƵŝŶĞĮŶĚŝŶŐ͘ŶŽƚŚĞƌƉƌĞĨĞƌƌĞĚĂƉƉƌŽĂĐŚƚŽŝŶƚĞŐƌĂƚĞ ŵƵůƟƉůĞŽŵŝĐƐĚĂƚĂŝƐĐĂůůĞĚŵĞƚĂͲĚŝŵĞŶƐŝŽŶĂůĂŶĂůLJƐŝƐ͕33 _{where raw data, transformed}

data or the underlying models are combined in a simultaneous analysis. Although ĐŽŶǀĞƌŐĞŶĐĞŽĨƚŚĞĚŝīĞƌĞŶƚƚLJƉĞƐŽĨĚĂƚĂŐĞŶĞƌĂƚĞƐĂŵŽƌĞĐŽŵƉůĞƚĞďŝŽůŽŐŝĐĂůƉŝĐƚƵƌĞ ŽĨƚŚĞƵŶĚĞƌůLJŝŶŐĞƟŽůŽŐLJŽĨĂĚŝƐĞĂƐĞ͕ŝƚĐŽŵĞƐǁŝƚŚŵĂŶLJĐŚĂůůĞŶŐĞƐ͘^ŽŌǁĂƌĞƚŽŽůƐ such as ATHENA,37_{'ůŵƉĂƚŚ}38 _{and Weka3}39_{ƵƐĞĚŝīĞƌĞŶƚĂƉƉƌŽĂĐŚĞƐƚŽŝŶƚĞŐƌĂƚĞŵƵůƟƉůĞ}

7

ĚĂƚĂƉĂƩĞƌŶƐ͕ďĂĐŬŐƌŽƵŶĚŶŽŝƐĞ͕ƐĂŵƉůĞƐŝnjĞƐĂŶĚĚĂƚĂŶŽƌŵĂůŝnjĂƟŽŶƚŚĂƚĚŝīĞƌďĞƚǁĞĞŶ ƚŚĞĚŝƐƟŶĐƚĚĂƚĂƚLJƉĞƐ͘ KĨ ƐƉĞĐŝĂů ŝŶƚĞƌĞƐƚ ŝƐ ƚŚĞ ŐĞŶĞƌĂƟŽŶ ŽĨ ŵƵůƟƉůĞ ĚĂƚĂ ůĞǀĞůƐ ĨŽƌ ƚŚĞ ƐĂŵĞ ŝŶĚŝǀŝĚƵĂůƐ͘&ŽƌŽƵƌƐƚƵĚŝĞƐ͕ĚŝƐƟŶĐƚWĐŽŚŽƌƚƐǁĞƌĞƵƐĞĚĨŽƌƚŚĞĚŝīĞƌĞŶƚŽŵŝĐƐƉƌŽũĞĐƚƐ͘ ,ŽǁĞǀĞƌ͕ĂŶƵůƟŵĂƚĞĚĞƐŝŐŶǁŽƵůĚĞŶĐŽŵƉĂƐƐŐĞŶŽŵŝĐƐ͕ĞƉŝŐĞŶŽŵŝĐƐ͕ƚƌĂŶƐĐƌŝƉƚŽŵŝĐƐ͕ ƉƌŽƚĞŽŵŝĐƐ ĂŶĚ ŵĞƚĂďŽůŽŵŝĐƐ ĚĂƚĂ ĨƌŽŵ ƚŚĞ ƐĂŵĞ ŝŶĚŝǀŝĚƵĂůƐ͘ /ƚ ŝƐ ĂŶƟĐŝƉĂƚĞĚ ƚŚĂƚ ƐƵĐŚ ĂƉƉƌŽĂĐŚĞƐ ĂƌĞ ŵŽƌĞ ƐĞŶƐŝƟǀĞ ƚŽ ĚĞƚĞĐƚ ĚŝƐĞĂƐĞͲƌĞůĂƚĞĚ ƐŝŐŶĂůƐ ĂƐ ŝƚ ĂůůŽǁƐ ĨŽƌ ŽďƐĞƌǀĂƟŽŶŽĨĚŝƌĞĐƚĞīĞĐƚƐŽĨĂīĞĐƚĞĚĨƵŶĐƟŽŶĂůƵŶŝƚƐďĞĐĂƵƐĞƚŚĞĚŝīĞƌĞŶƚŽŵŝĐƐĚĂƚĂ types can be linked on individual level. Although system biology approaches matching ƐĂŵƉůĞƐŽŶŝŶĚŝǀŝĚƵĂůůĞǀĞůŝƐƚŚĞƉƌĞĨĞƌƌĞĚĚĞƐŝŐŶ͕ƚŚĞŽŵŝĐƐƌĞƐĞĂƌĐŚĮĞůĚƐƟůůŚĂƐƚŽ ŽǀĞƌĐŽŵĞŵĂŶLJŽďƐƚĂĐůĞƐƚŽƉĞƌĨŽƌŵŝƚƉƌŽƉĞƌůLJ͘KŌĞŶŝƚŝƐĚŝĸĐƵůƚƚŽŽďƚĂŝŶƐƵĸĐŝĞŶƚ ƟƐƐƵĞƚŽƉĞƌĨŽƌŵŵƵůƟƉůĞŽŵŝĐƐĞdžƉĞƌŝŵĞŶƚƐ͘ŶĚĂůƚŚŽƵŐŚŝŶƚĞŐƌĂƟŽŶŽĨĚŝƐƟŶĐƚŽŵŝĐƐ ĚĂƚĂƚLJƉĞƐĨŽƌƚŚĞƐĂŵĞŝŶĚŝǀŝĚƵĂůǁŽƵůĚďĞƉŽƐƐŝďůĞǁŝƚŚďŝŽŝŶĨŽƌŵĂƟĐƐƚŽŽůƐƐƵĐŚĂƐ d,E͕ƚŚĞĚĂƚĂŝŶƚĞŐƌĂƟŽŶŵĞƚŚŽĚƐŚĂǀĞŽŶůLJũƵƐƚƐƚĂƌƚĞĚƚŽĚĞǀĞůŽƉĂŶĚĐƵƌƌĞŶƚůLJŶŽ ŐĞŶĞƌĂůĐŽŶƐĞŶƐƵƐĞdžŝƐƚƐ͘KŶĞŽĨƚŚĞŵĂũŽƌŝƐƐƵĞƐƚŽĂĚĚƌĞƐƐŝƐƚŽĐŚŽŽƐĞƚŚĞĂƉƉƌŽƉƌŝĂƚĞ underlying model to test for the disease of interest. As system-based approach studies ĂƌĞƌĞůĂƟǀĞůLJŶŽǀĞů͕ǁĞůĂĐŬĂĚĞƋƵĂƚĞƉƵďůŝƐŚĞĚĞdžĂŵƉůĞƐĨŽƌWƚŚĞƌĞĨŽƌĞƉƌĞĚŝĐƟŶŐƚŚĞ ŵŽĚĞůŝƐƵŶĐĞƌƚĂŝŶ͘ŽŵďŝŶŝŶŐƚŚĞĚŝƐƟŶĐƚĚĂƚĂŝŶƚĞŐƌĂƟŽŶƚŽŽůƐǁŝůůƉƌĞƐƵŵĂďůLJƐƵƉƉůLJ the most comprehensive analysis method guiding us to an improved understanding of PD ƉĂƚŚŽŐĞŶĞƐŝƐďLJǀŝƐƵĂůŝnjŝŶŐƚŚĞĂīĞĐƚĞĚĐŽŵƉůĞdžďŝŽůŽŐLJƐLJƐƚĞŵ͘

WŽƐƚt^ĞƌĂ͗ĨƵƚƵƌĞŽĨWŐĞŶĞƟĐƐ

dŚĞ ĚŝƐĐŽǀĞƌLJ ŽĨ ƌĂƌĞ ǀĂƌŝĂŶƚƐ ǁŝƚŚ ŶŽŶͲĐŽŶǀĞŶƟŽŶĂů t^ ƐƚƵĚŝĞƐ ŝŶ ĐŽŚŽƌƚƐ ƵƐŝŶŐ ƵŶƌĞůĂƚĞĚ ƐƵďũĞĐƚƐ͕ ďĞƐŝĚĞƐ ƚŚĞ ƚƌĂĚŝƟŽŶĂů ůŝŶŬĂŐĞ ĂŶĂůLJƐŝƐ ǁŝƚŚŝŶ ĨĂŵŝůŝĞƐ͕ ŚĂƐ ďĞĞŶ successful in a few neurologic disorders.40,41_{,ŽǁĞǀĞƌ͕ŝŶŐĞŶĞƌĂůƚŚĞŐĞŶĞƟĐƌĞƐĞĂƌĐŚĮĞůĚ}

ŚĂĚŚŝŐŚĞƌĞdžƉĞĐƚĂƟŽŶƐĨƌŽŵt^ĂƚƚŚĞďĞŐŝŶŶŝŶŐŽĨƚŚĞE'^ĞƌĂ͕ĂƐŝƚǁĂƐĂŶƟĐŝƉĂƚĞĚ that many novel causal variants would be easily revealed with simple analysis methods. &ŽƌW͕ĐŽŶƐĞƌǀĂƟǀĞĐĂůĐƵůĂƟŽŶƐƉƌĞĚŝĐƚƚŚĂƚŽŶůLJϭϬйŽĨƚŚĞŚĞƌŝƚĂďŝůŝƚLJŝƐĞdžƉůĂŝŶĞĚďLJ ŬŶŽǁŶ ŐĞŶĞƟĐ ĐĂƵƐĞƐ͘42_{ dŚŝƐ ƐƵŐŐĞƐƚƐ ƚŚĂƚ ƚŚĞ ĨŽĐƵƐ ŽĨ ƚŚĞ W ŐĞŶĞƟĐƐ ƌĞƐĞĂƌĐŚ ĮĞůĚ}

ƐŚŽƵůĚďĞƐǁŝƚĐŚĞĚƚŽĂĚŝīĞƌĞŶƚƚLJƉĞŽĨŐĞŶĞƟĐĚĞĨĞĐƚŽƌǁĞƐŝŵƉůLJĂƌĞůĂĐŬŝŶŐƚŚĞŵĞĂŶƐ ƚŽŐĞŶĞƌĂƚĞĚĂƚĂƐĞƚƐŽĨƐƵĸĐŝĞŶƚƐĂŵƉůĞƐŝnjĞ͘^ŽŚŽǁƚŽƵŶĐŽǀĞƌƚŚĞƌĞŵĂŝŶŝŶŐϵϬй͍

7

achievable to combine WES datasets with other PD or brain-related datasets that will lead ƚŽŶŽǀĞůŐĞŶĞƟĐŝŶƐŝŐŚƚƐ͘

tŚŽůĞŐĞŶŽŵĞƐĞƋƵĞŶĐŝŶŐ;t'^ͿŝƐŐƌĂĚƵĂůůLJďĞĐŽŵŝŶŐƚŚĞŐŽůĚƐƚĂŶĚĂƌĚƚŽƐƚƵĚLJ ǀĂƌŝĂŶƚƐŝŶĂŐĞŶŽŵĞͲǁŝĚĞĨĂƐŚŝŽŶ͘dŚĞt'^ƚĞĐŚŶŽůŽŐLJĮĞůĚŝƐĞǀŽůǀŝŶŐďLJĚĞǀĞůŽƉŝŶŐ ŵĞƚŚŽĚƐ ƚŽ ƐĞƋƵĞŶĐĞ ůŽŶŐĞƌ ƌĞĂĚƐ͕ ĚĞĐƌĞĂƐŝŶŐ ƐĞƋƵĞŶĐŝŶŐ ĞƌƌŽƌƐ ĂŶĚ ŐĞŶĞƌĂƟŶŐ protocols for single cells.43,44_{KĨƐƉĞĐŝĂůŝŶƚĞƌĞƐƚŝƐƐŝŶŐůĞͲĐĞůůƐĞƋƵĞŶĐŝŶŐĂƐŝƚĂůůŽǁƐƚŽ}

ƐƚƵĚLJŵŽƐĂŝĐŝƐŵ͕ƚŚĞĞdžŝƐƚĞŶĐĞŽĨƚǁŽŽƌŵŽƌĞŐĞŶĞƟĐĂůůLJĚŝƐƟŶĐƚĐĞůůƉŽƉƵůĂƟŽŶƐǁŝƚŚŝŶ a single organism. In 2013, a study on mosaicism in neurons revealed that at least 13% of neuronal cells have de novo CNVs.45_{/ŶƉĞƌƐƉĞĐƟǀĞŽĨW͕ƐĞƋƵĞŶĐŝŶŐƐŝŶŐůĞͲĐĞůůƐĨƌŽŵ}

ƚŚĞƐƵďƐƚĂŶƟĂŶŝŐƌĂǁŽƵůĚƉŽƚĞŶƟĂůůLJƌĞǀĞĂůĚĞŶŽǀŽŵƵƚĂƟŽŶƐ͕ƉƵƚĂƟǀĞůLJĞdžƉůĂŝŶŝŶŐƚŚĞ ǀƵůŶĞƌĂďŝůŝƚLJĨŽƌŶĞƵƌŽŶĂůĐĞůůůŽƐƐŽĨƚŚŝƐƐƉĞĐŝĮĐƌĞŐŝŽŶ͘EŽƚƐƉĞĐŝĮĐƚŽƐŝŶŐůĞͲĐĞůůt'^ ďƵƚĂƉƉůŝĐĂďůĞƚŽt'^ŝŶŐĞŶĞƌĂů͕ŝƐƚŚĞƐĞĂƌĐŚĨŽƌƐƚƌƵĐƚƵƌĂůĂŶĚŶŽŶͲĐŽĚŝŶŐǀĂƌŝĂƟŽŶ͘ ^ƚƌƵĐƚƵƌĂů ǀĂƌŝĂƟŽŶ ŵŝŐŚƚ ĂīĞĐƚ ůĂƌŐĞ ƌĞŐŝŽŶƐ ŽĨ ƚŚĞ ŐĞŶŽŵĞ͕ ƉŽƚĞŶƟĂůůLJ ĂīĞĐƟŶŐ ƚŚĞ ĨƵŶĐƟŽŶŽĨŵƵůƟƉůĞŐĞŶĞƐ͘46,47_{t^ŝƐŶŽƚŝĚĞĂůƚŽďĞƵƟůŝnjĞĚĨŽƌĐĂůůŝŶŐƐƚƌƵĐƚƵƌĂůǀĂƌŝĂŶƚƐ͕}

since large parts of the genome are missing, and the non-coding regions are not covered. ƐƐƚƌƵĐƚƵƌĂůǀĂƌŝĂŶƚƐŚĂǀĞďĞĞŶƐŚŽǁŶƚŽĐĂƵƐĞďŽƚŚDĞŶĚĞůŝĂŶĂƐĐŽŵƉůĞdžĚŝƐĞĂƐĞƐ͕48

ĂŶĚ W ŚĂƐ ďĞĞŶ ĂƐƐŽĐŝĂƚĞĚ ƚŽ ŵƵůƟƉůĞ EsƐ ŝŶ SNCA, parkin, PINK1 and DJ-1,49 _{it is}

ƉůĂƵƐŝďůĞƚŚĂƚŵŽƌĞƵŶĚŝƐĐŽǀĞƌĞĚƐƚƌƵĐƚƵƌĂůǀĂƌŝĂƟŽŶĐĂƵƐĞƐW͘dŚĞŝŵƉůĞŵĞŶƚĂƟŽŶŽĨ ƚŚŝƌĚͲŐĞŶĞƌĂƟŽŶt'^ƚĞĐŚŶŝƋƵĞƐ͕ƐƵĐŚĂƐůŽŶŐƌĞĂĚƐĞƋƵĞŶĐŝŶŐƚŚĂƚĨĂĐŝůŝƚĂƚĞƐƵŶŝƋƵĞ alignment of the reads,50,51_{ǁŽƵůĚĞŶŚĂŶĐĞƚŚĞŝĚĞŶƟĮĐĂƟŽŶŽĨƐƚƌƵĐƚƵƌĂůǀĂƌŝĂŶƚƐĂŶĚƚŚĞ}

ĞƐƚĂďůŝƐŚŵĞŶƚŽĨƌĞƉĞƟƟǀĞƌĞŐŝŽŶƐ͘&ŝŶĂůůLJ͕ŶŽŶͲĐŽĚŝŶŐƌĞŐŝŽŶƐĂƌĞŵŽƐƚůLJƵŶĞdžƉůŽƌĞĚ͘ ŽŶƐŝĚĞƌŝŶŐƚŚĂƚĂƉƉƌŽdžŝŵĂƚĞůLJϭйŽĨƚŚĞŐĞŶŽŵĞĐŽŶƐŝƐƚƐŽĨĐŽĚŝŶŐ ƐĞƋƵĞŶĐĞƐ͕52 _the

ƌĞŐŝŽŶƐ ƚŚĂƚ ĂƌĞ ƚĂƌŐĞƚĞĚ ǁŝƚŚ t^͕ ŝƚ ƐƵŐŐĞƐƚƐ ƚŚĞƌĞ ŝƐ ƐƟůů ϵϵй ŽĨ ƚŚĞ ŐĞŶŽŵĞ ƚŚĂƚ ŚĂƐ ďĞĞŶ ƐƚƵĚŝĞĚ ƉŽŽƌůLJ ŝŶ ƌĞůĂƟŽŶ ƚŽ W͘ Ɛ Ă ƌĞĐĞŶƚ ƐƚƵĚLJ ƌĞǀĞĂůĞĚ ƚŚĞ ĨƵŶĐƟŽŶĂů ĐŽŶŶĞĐƟŽŶďĞƚǁĞĞŶĂŶŽŶͲĐŽĚŝŶŐǀĂƌŝĂŶƚŝŶĂŶSNCA enhancer and PD,53_{ŝƚŝƐĂŶƟĐŝƉĂƚĞĚ}

7

/W'ŝƐƚŚĞůĂƌŐĞƐƚWŐĞŶĞƟĐƐĐŽŶƐŽƌƟƵŵĂŶĚƚŚĞŝƌƐŽƵƌĐĞƐĂƌĞĐůŽƐĞƚŽĨƵůůLJĞdžŚĂƵƐƚĞĚ ǁŝƚŚĂƚŽƚĂůŽĨΕϮϱ͕ϬϬϬĐĂƐĞƐ͘/ƚŝƐƋƵĞƐƟŽŶĂďůĞŝĨĞdžƚĞŶĚŝŶŐĐŽůůĂďŽƌĂƟŽŶƐǁŝůůŝŶĐƌĞĂƐĞ ƐĂŵƉůĞƐŝnjĞƐƐƵďƐƚĂŶƟĂůůLJƚŽƌĞĂĐŚƐƵĸĐŝĞŶƚƉŽǁĞƌĨŽƌĚĞƚĞĐƟŽŶŽĨŶŽǀĞůƌĂƌĞŐĞŶĞƟĐ ĨĂĐƚŽƌƐ͘ KŶĞ ƐŽůƵƟŽŶ ŵŝŐŚƚ ďĞ ƚŽ ĐŽůůĞĐƚ ŐĞŶĞƟĐ W ĚĂƚĂ ĂĐƌŽƐƐ ĞƚŚŶŝĐĂůůLJ ĚŝīĞƌĞŶƚ ƉŽƉƵůĂƟŽŶƐ͘  ƐĞĐŽŶĚ ƐƚƌĂƚĞŐLJ ĞŶĐŽŵƉĂƐƐĞƐ ƚŚĞ ƌĞͲĞdžĂŵŝŶĂƟŽŶ ŽĨ ƚŚĞ ĞdžŝƐƟŶŐ 't^ ĚĂƚĂďLJĨŽĐƵƐŝŶŐŽŶƐĞŵŝͲƐŝŐŶŝĮĐĂŶƚŚŝƚƐŝŶĐŽŵďŝŶĂƟŽŶǁŝƚŚĨƵŶĐƟŽŶĂůĂŶŶŽƚĂƟŽŶĚĂƚĂ͕ ƉĞƌĨŽƌŵŝŶŐĂƐLJƐƚĞŵͲďĂƐĞĚĂƉƉƌŽĂĐŚĂƐĚŝƐĐƵƐƐĞĚƉƌĞǀŝŽƵƐůLJ͘'ĞŶŽ^ŬLJůŝŶĞŝƐĂŐĞŶĞƟĐ ƚŽŽůƚŚĂƚŝŶƚĞŐƌĂƚĞƐ't^ĚĂƚĂǁŝƚŚƟƐƐƵĞͲƐƉĞĐŝĮĐĨƵŶĐƟŽŶĂůƉƌĞĚŝĐƟŽŶƐ͘55_{dŚĞĨƵŶĐƟŽŶĂů} ŝŶĨŽƌŵĂƟŽŶ ŝƐ ďĂƐĞĚ ŽŶ ĞƉŝŐĞŶŽŵŝĐ ĚĂƚĂ ĂŶĚ ĂƉƉůŝĐĂƟŽŶ ŽĨ ƚŚĞ ƚŽŽů ĐŽƵůĚ ƉŽƚĞŶƟĂůůLJ reveal novel PD risk loci.

ĞƐŝĚĞƐƚŚĞŝĚĞŶƟĮĐĂƟŽŶŽĨŶŽǀĞůWƌŝƐŬůŽĐŝ͕ŝƚŝƐĞƐƐĞŶƟĂůƚŽĐŽŶƟŶƵĞƚŽĞdžƉůŽƌĞ the known PD risk loci to understand how these associated LD blocks are associated to W͘ZĞƐĞƋƵĞŶĐŝŶŐŽĨĂůů>ďůŽĐŬƐǁŽƵůĚďĞĂǀĂůƵĂďůĞƐƚƌĂƚĞŐLJ ƚŽƉŝŶƉŽŝŶƚƚŚĞĐĂƵƐĂů ǀĂƌŝĂŶƚ ĂŶĚ ŐĞŶĞ͘ ^ƵĐĐĞƐƐĨƵů ƐƚƵĚŝĞƐ ŚĂǀĞ ĨŽůůŽǁĞĚ ƚŚŝƐ ƐƚƌĂƚĞŐLJ ĂŶĚ ŝĚĞŶƟĮĞĚ ĐĂƵƐĂů ǀĂƌŝĂŶƚƐ ĨŽƌ ŝŶŇĂŵŵĂƚŽƌLJ ďŽǁĞů ĚŝƐĞĂƐĞ ĂŶĚ ƐĐŚŝnjŽƉŚƌĞŶŝĂ͘56-58_{ &Žƌ W͕ ƐƵĐŚ Ă ƐƚƵĚLJ} ŝƐ ĐƵƌƌĞŶƚůLJ ŽŶŐŽŝŶŐ ĂŶĚ ǁŝůů ƉƵƚĂƟǀĞůLJ ĞdžƉůĂŝŶ ƚƌƵĞ ĐĂƵƐĂů ǀĂƌŝĂŶƚƐ ĨŽƌ Ă ĨĞǁ ůŽĐŝ͘ Ŷ ĂůƚĞƌŶĂƟǀĞĂƉƉƌŽĂĐŚƚŽĐŽŵƉƌĞŚĞŶĚƚŚĞƵŶĚĞƌůLJŝŶŐŵŽůĞĐƵůĂƌŵĞĐŚĂŶŝƐŵƐŽĨƚŚĞWƌŝƐŬ ůŽĐŝ͕ŝƐƚŽĨƵŶĐƟŽŶĂůůLJĨŽůůŽǁͲƵƉĂůůŐĞŶĞƐƵŶĚĞƌŶĞĂƚŚƚŚĞ't^ƉĞĂŬƐ͘ůƚŚŽƵŐŚƐƵĐŚ Ă ƉƌŽũĞĐƚ ǁŽƵůĚ ƌĞƋƵŝƌĞ ĚĞĚŝĐĂƟŽŶ ĚƵĞ ƚŽ ŝƚƐ ĞůĂďŽƌĂƚĞ ĂŵŽƵŶƚ ŽĨ ǁŽƌŬ͕ ŝƚ ŝƐ ĨĞĂƐŝďůĞ ǁŝƚŚƚŚĞƌĞĐĞŶƚĚĞǀĞůŽƉŵĞŶƚƐŝŶŚŝŐŚͲƚŚƌŽƵŐŚƉƵƚĨƵŶĐƟŽŶĂůƐĐƌĞĞŶŝŶŐĞdžƉĞƌŝŵĞŶƚƐ͘/Ŷ this regard, an inspiring study has suggested RAB29 and GAK as causal genes of 2 PD ƌŝƐŬ ůŽĐŝ ďLJ ƉĞƌĨŽƌŵŝŶŐ Ă ůĂƌŐĞ ĨƵŶĐƟŽŶĂů ƐĐƌĞĞŶŝŶŐ ĞīŽƌƚ ƐĞĂƌĐŚŝŶŐ ĨŽƌ ŝŶƚĞƌĂĐƚŽƌƐ ŽĨ

LRRK2.59_{ŽŵďŝŶŝŶŐƚŚĞŝƌŝŶƚĞƌĂĐƚŽƌƐǁŝƚŚW't^ĚĂƚĂĞdžƉŽƐĞĚƚŚĞϮŐĞŶĞƐ͘,ŽǁĞǀĞƌ͕}

ŽŶĞƐŚŽƵůĚďĞĂǁĂƌĞƚŚĂƚƐƵĐŚĨƵŶĐƟŽŶĂůĂƉƉƌŽĂĐŚĞƐĐŽƵůĚƐƟůůŵŝƐƐƚŚĞWŐĞŶĞƐƚŚĂƚ ĂƌĞůŽĐĂƚĞĚŽƵƚƐŝĚĞƚŚĞĂƐƐŽĐŝĂƚĞĚ>ďůŽĐŬŽĨǁŚŝĐŚĞdžƉƌĞƐƐŝŽŶŝƐƌĞŐƵůĂƚĞĚďLJĂĐĂƵƐĂů variant within the associated locus.

ƵƚŽŵĂƚĞĚ ŚŝŐŚͲƚŚƌŽƵŐŚƉƵƚ ĨƵŶĐƟŽŶĂů ƐĐƌĞĞŶŝŶŐ ĞīŽƌƚƐ ŚĂǀĞ ƚŚĞ ƉŽƚĞŶƟĂů ƚŽƵŶĐŽǀĞƌŐĞŶĞƟĐĂŶĚďŝŽůŽŐŝĐĂůŝŶƐŝŐŚƚƐǁŚŝĐŚůŝĞƐďĞLJŽŶĚƚŚĞůŝŵŝƚƐŽĨƉƵƌĞŐĞŶĞƟĐ ƐƚƵĚŝĞƐ͘dŚĞĨƵŶĐƟŽŶĂůƐĐƌĞĞŶŝŶŐƌĞƐĞĂƌĐŚŽŶ,^W͕34_{ƚŚĞĂďŽǀĞŵĞŶƟŽŶĞĚLRRK2 interactor}

study,59 _{but also our own study in chapter 6, show the ingenuity of these approaches to}

ŽǀĞƌĐŽŵĞƚŚĞŽďƐƚĂĐůĞƐǁĞĞdžƉĞƌŝĞŶĐĞǁŚĞŶŝŶƚĞƌƉƌĞƟŶŐŐĞŶŽŵĞͲǁŝĚĞƌĞƐƵůƚƐ͕ďLJƵƐŝŶŐ ďƌŽĂĚͲƐĐĂůĞ ĨƵŶĐƟŽŶĂů ĞdžƉĞƌŝŵĞŶƚƐ͘ &ƵƌƚŚĞƌŵŽƌĞ͕ ĂƵƚŽŵĂƟŶŐ ĚŝīĞƌĞŶƟĂƟŽŶ ƉƌŽƚŽĐŽůƐ ŽĨŝŶĚƵĐĞĚƉůƵƌŝƉŽƚĞŶƚƐƚĞŵĐĞůůƐĂŶĚZ/^WZƚĞĐŚŶŽůŽŐLJ͕60,61 _{mimicking the disease state}

7

7

ϭ͘ ƌĂƐ :͕ 'ƵĞƌƌĞŝƌŽ Z͕ ,ĂƌĚLJ :͘ ^ŶĂƉ^ŚŽƚ͗ 'ĞŶĞƟĐƐŽĨWĂƌŬŝŶƐŽŶ͛ƐĚŝƐĞĂƐĞ͘CellϮϬϭϱ͖ 160(3): 570-.e1. Ϯ͘<ĞůůĞƌD&͕^ĂĂĚD͕ƌĂƐ:͕ĞƚĂů͘hƐŝŶŐŐĞŶŽŵĞͲ ǁŝĚĞ ĐŽŵƉůĞdž ƚƌĂŝƚ ĂŶĂůLJƐŝƐ ƚŽ ƋƵĂŶƟĨLJ ͚ŵŝƐƐŝŶŐ ŚĞƌŝƚĂďŝůŝƚLJ͛ ŝŶ WĂƌŬŝŶƐŽŶ͛Ɛ disease. ,ƵŵĂŶŵŽůĞĐƵůĂƌŐĞŶĞƟĐƐϮϬϭϮ͖ 21(22): 4996-5009. ϯ͘,ĂŵnjĂd,͕WĂLJĂŵŝ,͘dŚĞŚĞƌŝƚĂďŝůŝƚLJŽĨƌŝƐŬ and age at onset of Parkinson’s disease ĂŌĞƌ ĂĐĐŽƵŶƟŶŐ ĨŽƌ ŬŶŽǁŶ ŐĞŶĞƟĐ ƌŝƐŬ factors. :ŽƵƌŶĂů ŽĨ ŚƵŵĂŶ ŐĞŶĞƟĐƐ ϮϬϭϬ͖ 55(4): 241-3.

ϰ͘ dƌŝŶŚ :͕ &ĂƌƌĞƌ D͘ ĚǀĂŶĐĞƐ ŝŶ ƚŚĞ ŐĞŶĞƟĐƐ of Parkinson disease. Nature reviews

NeurologyϮϬϭϯ͖ϵ;ϴͿ͗ϰϰϱͲϱϰ͘

ϱ͘&ƵŶĂLJĂŵĂD͕KŚĞ<͕ŵŽd͕ĞƚĂů͘,,Ϯ ŵƵƚĂƟŽŶƐ ŝŶ ĂƵƚŽƐŽŵĂů ĚŽŵŝŶĂŶƚ ůĂƚĞͲ onset Parkinson’s disease: a genome-wide linkage and sequencing study. Lancet

neurology 2015. ϲ͘ ^ŝŵŽŶͲ^ĂŶĐŚĞnj :͕ ^ĐŚƵůƚĞ ͕ ƌĂƐ :D͕ Ğƚ Ăů͘ 'ĞŶŽŵĞͲǁŝĚĞ ĂƐƐŽĐŝĂƟŽŶ ƐƚƵĚLJ ƌĞǀĞĂůƐ ŐĞŶĞƟĐƌŝƐŬƵŶĚĞƌůLJŝŶŐWĂƌŬŝŶƐŽŶ͛ƐĚŝƐĞĂƐĞ͘ EĂƚƵƌĞŐĞŶĞƟĐƐϮϬϬϵ͖ϰϭ;ϭϮͿ͗ϭϯϬϴͲϭϮ͘ ϳ͘ /ŶƚĞƌŶĂƟŽŶĂů WĂƌŬŝŶƐŽŶ͛Ɛ ŝƐĞĂƐĞ 'ĞŶŽŵŝĐƐ ŽŶƐŽƌƟƵŵ͕tĞůůĐŽŵĞdƌƵƐƚĂƐĞŽŶƚƌŽů ŽŶƐŽƌƟƵŵϮ͘  ƚǁŽͲƐƚĂŐĞ ŵĞƚĂͲĂŶĂůLJƐŝƐ ŝĚĞŶƟĮĞƐƐĞǀĞƌĂůŶĞǁůŽĐŝĨŽƌWĂƌŬŝŶƐŽŶ͛Ɛ disease. W>Ž^ ŐĞŶĞƟĐƐ ϮϬϭϭ͖ ϳ;ϲͿ͗ e1002142. ϴ͘ EĂůůƐ D͕ WůĂŐŶŽů s͕ ,ĞƌŶĂŶĚĞnj '͕ Ğƚ Ăů͘ /ŵƉƵƚĂƟŽŶ ŽĨ ƐĞƋƵĞŶĐĞ ǀĂƌŝĂŶƚƐ ĨŽƌ ŝĚĞŶƟĮĐĂƟŽŶ ŽĨ ŐĞŶĞƟĐ ƌŝƐŬƐ ĨŽƌ Parkinson’s disease: a meta-analysis of ŐĞŶŽŵĞͲǁŝĚĞ ĂƐƐŽĐŝĂƟŽŶ ƐƚƵĚŝĞƐ͘ Lancet ϮϬϭϭ͖ϯϳϳ;ϵϳϲϲͿ͗ϲϰϭͲϵ͘

ϵ͘ EĂůůƐ D͕ WĂŶŬƌĂƚnj E͕ >ŝůů D͕ Ğƚ Ăů͘ >ĂƌŐĞͲ scale meta-analysis of genome-wide ĂƐƐŽĐŝĂƟŽŶĚĂƚĂŝĚĞŶƟĮĞƐƐŝdžŶĞǁƌŝƐŬůŽĐŝ for Parkinson’s disease. EĂƚƵƌĞ ŐĞŶĞƟĐƐ

ϮϬϭϰ͖ϰϲ;ϵͿ͗ϵϴϵͲϵϯ͘

ϭϬ͘ŝũŬƐƚƌĂ͕/ŶŐƌĂƐƐŝĂ͕ĚĞDĞŶĞnjĞƐZy͕Ğƚ Ăů͘ǀŝĚĞŶĐĞĨŽƌ/ŵŵƵŶĞZĞƐƉŽŶƐĞ͕džŽŶĂů LJƐĨƵŶĐƟŽŶ ĂŶĚ ZĞĚƵĐĞĚ ŶĚŽĐLJƚŽƐŝƐ ŝŶ ƚŚĞ ^ƵďƐƚĂŶƟĂ EŝŐƌĂ ŝŶ ĂƌůLJ ^ƚĂŐĞ Parkinson’s Disease. PloS oneϮϬϭϱ͖ϭϬ;ϲͿ͗ e0128651. ϭϭ͘ <ůĞŝŶ ͕ tĞƐƚĞŶďĞƌŐĞƌ ͘ 'ĞŶĞƟĐƐ ŽĨ Parkinson’s disease. ŽůĚ ^ƉƌŝŶŐ ,ĂƌďŽƌ ƉĞƌƐƉĞĐƟǀĞƐ ŝŶ ŵĞĚŝĐŝŶĞ ϮϬϭϮ͖ Ϯ;ϭͿ͗ a008888. ϭϮ͘ <ŝĞnjƵŶ ͕ 'ĂƌŝŵĞůůĂ <͕ Ž Z͕ Ğƚ Ăů͘ džŽŵĞ ƐĞƋƵĞŶĐŝŶŐ ĂŶĚ ƚŚĞ ŐĞŶĞƟĐ ďĂƐŝƐ ŽĨ ĐŽŵƉůĞdž ƚƌĂŝƚƐ͘ EĂƚƵƌĞ ŐĞŶĞƟĐƐ ϮϬϭϮ͖ 44(6): 623-30. ϭϯ͘ <ŝƌĐŚĞƌ D͕ tŝƩĞŶ D͕ :ĂŝŶ W͕ K͛ZŽĂŬ :͕ ŽŽƉĞƌ 'D͘  ŐĞŶĞƌĂů ĨƌĂŵĞǁŽƌŬ ĨŽƌ ĞƐƟŵĂƟŶŐ ƚŚĞ ƌĞůĂƟǀĞ ƉĂƚŚŽŐĞŶŝĐŝƚLJ ŽĨ ŚƵŵĂŶŐĞŶĞƟĐǀĂƌŝĂŶƚƐ͘ϮϬϭϰ͖ϰϲ;ϯͿ͗ϯϭϬͲ 5.

14. 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

ϭϱ͘ /ŽŶŝƚĂͲ>ĂnjĂ /͕ ĂƉĂŶƵ D͕ Ğ ZƵďĞŝƐ ^͕ DĐĂůůƵŵ <͕ ƵdžďĂƵŵ :͘ /ĚĞŶƟĮĐĂƟŽŶ of rare causal variants in sequence-ďĂƐĞĚ ƐƚƵĚŝĞƐ͗ ŵĞƚŚŽĚƐ ĂŶĚ ĂƉƉůŝĐĂƟŽŶƐ to VPS13B, a gene involved in Cohen ƐLJŶĚƌŽŵĞĂŶĚĂƵƟƐŵ͘W>Ž^ŐĞŶĞƟĐƐϮϬϭϰ͖ 10(12): e1004729.

ϭϲ͘ >ŝŶ tz͘ ĞLJŽŶĚ ZĂƌĞͲsĂƌŝĂŶƚ ƐƐŽĐŝĂƟŽŶ dĞƐƟŶŐ͗WŝŶƉŽŝŶƟŶŐZĂƌĞĂƵƐĂůsĂƌŝĂŶƚƐŝŶ Case-Control Sequencing Study. ^ĐŝĞŶƟĮĐ

7

ŶĂďƵŶĚĂŶĐĞŽĨƌĂƌĞĨƵŶĐƟŽŶĂů ǀĂƌŝĂŶƚƐ in 202 drug target genes sequenced in 14,002 people. ^ĐŝĞŶĐĞ ;EĞǁ zŽƌŬ͕ EzͿ ϮϬϭϮ͖ϯϯϳ;ϲϬϵϬͿ͗ϭϬϬͲϰ͘ ϭϵ͘dĞŶŶĞƐƐĞŶ:͕ŝŐŚĂŵt͕K͛ŽŶŶŽƌd͕Ğƚ Ăů͘ǀŽůƵƟŽŶĂŶĚĨƵŶĐƟŽŶĂůŝŵƉĂĐƚŽĨƌĂƌĞ ĐŽĚŝŶŐǀĂƌŝĂƟŽŶĨƌŽŵĚĞĞƉƐĞƋƵĞŶĐŝŶŐŽĨ ŚƵŵĂŶ ĞdžŽŵĞƐ͘ ^ĐŝĞŶĐĞ ;EĞǁ zŽƌŬ͕ EzͿ ϮϬϭϮ͖ϯϯϳ;ϲϬϵϬͿ͗ϲϰͲϵ͘ ϮϬ͘ K͛ŽŶŶŽƌ d͕ <ŝĞnjƵŶ ͕ ĂŵƐŚĂĚ D͕ Ğƚ Ăů͘ &ŝŶĞͲƐĐĂůĞ ƉĂƩĞƌŶƐ ŽĨ ƉŽƉƵůĂƟŽŶ ƐƚƌĂƟĮĐĂƟŽŶ ĐŽŶĨŽƵŶĚ ƌĂƌĞ ǀĂƌŝĂŶƚ ĂƐƐŽĐŝĂƟŽŶ ƚĞƐƚƐ͘ PloS one ϮϬϭϯ͖ ϴ;ϳͿ͗ e65834.

21. Boomsma DI, Wijmenga C, Slagboom EP, Ğƚ Ăů͘ dŚĞ 'ĞŶŽŵĞ ŽĨ ƚŚĞ EĞƚŚĞƌůĂŶĚƐ͗ design, and project goals. European

ũŽƵƌŶĂů ŽĨ ŚƵŵĂŶ ŐĞŶĞƟĐƐ ͗ :,' ϮϬϭϰ͖

22(2): 221-7.

ϮϮ͘ DĂƚŚŝĞƐŽŶ /͕ DĐsĞĂŶ '͘ ŝīĞƌĞŶƟĂů confounding of rare and common variants ŝŶƐƉĂƟĂůůLJƐƚƌƵĐƚƵƌĞĚƉŽƉƵůĂƟŽŶƐ͘Nature

ŐĞŶĞƟĐƐϮϬϭϮ͖ϰϰ;ϯͿ͗ϮϰϯͲϲ͘

Ϯϯ͘ ƵŬ K͕ ^ĐŚĂīŶĞƌ ^&͕ ^ĂŵŽĐŚĂ <͕ Ğƚ Ăů͘ Searching for missing heritability: ĚĞƐŝŐŶŝŶŐƌĂƌĞǀĂƌŝĂŶƚĂƐƐŽĐŝĂƟŽŶƐƚƵĚŝĞƐ͘ WƌŽĐĞĞĚŝŶŐƐ ŽĨ ƚŚĞ EĂƟŽŶĂů ĐĂĚĞŵLJ ŽĨ ^ĐŝĞŶĐĞƐ ŽĨ ƚŚĞ hŶŝƚĞĚ ^ƚĂƚĞƐ ŽĨ ŵĞƌŝĐĂ ϮϬϭϰ͖ϭϭϭ;ϰͿ͗ϰϱϱͲϲϰ͘ Ϯϰ͘>ĞĞ^͕ďĞĐĂƐŝƐ'Z͕ŽĞŚŶŬĞD͕>ŝŶy͘ZĂƌĞͲ ǀĂƌŝĂŶƚĂƐƐŽĐŝĂƟŽŶĂŶĂůLJƐŝƐ͗ƐƚƵĚLJĚĞƐŝŐŶƐ ĂŶĚ ƐƚĂƟƐƟĐĂů ƚĞƐƚƐ͘ ŵĞƌŝĐĂŶ ũŽƵƌŶĂů ŽĨ ŚƵŵĂŶŐĞŶĞƟĐƐϮϬϭϰ͖ϵϱ;ϭͿ͗ϱͲϮϯ͘ Ϯϱ͘ƵƐŚt^͕DŽŽƌĞ:,͘ŚĂƉƚĞƌϭϭ͗'ĞŶŽŵĞͲ tŝĚĞ ƐƐŽĐŝĂƟŽŶ ^ƚƵĚŝĞƐ͘ PLoS ĐŽŵƉƵƚĂƟŽŶĂůďŝŽůŽŐLJϮϬϭϮ͖ϴ;ϭϮͿ͘ Ϯϲ͘WĂƌŬŝŶƐŽŶWƌŽŐƌĞƐƐŝŽŶDĂƌŬĞƌ/ŶŝƟĂƟǀĞdŚĞ WĂƌŬŝŶƐŽŶ WƌŽŐƌĞƐƐŝŽŶ DĂƌŬĞƌ /ŶŝƟĂƟǀĞ (PPMI). Progress in neurobiology ϮϬϭϭ͖ 95(4): 629-35. Ϯϳ͘ dƌLJŬĂ <͕ ,ĂŽ >͕ ^ƚƵƌĐŬĞ ͕ Ğƚ Ăů͘ E/͛Ɛ ĂƚĂďĂƐĞ ŽĨ 'ĞŶŽƚLJƉĞƐ ĂŶĚ WŚĞŶŽƚLJƉĞƐ͗ Ěď'ĂW͘ EƵĐůĞŝĐ ĂĐŝĚƐ ƌĞƐĞĂƌĐŚ ϮϬϭϰ͖ 42(Database issue): D975-9. Ϯϴ͘ >ĂƉƉĂůĂŝŶĞŶ /͕ ůŵĞŝĚĂͲ<ŝŶŐ :͕ <ƵŵĂŶĚƵƌŝ s͕ĞƚĂů͘dŚĞƵƌŽƉĞĂŶ'ĞŶŽŵĞͲƉŚĞŶŽŵĞ Archive of human data consented for biomedical research. EĂƚƵƌĞ ŐĞŶĞƟĐƐ ϮϬϭϱ͖ϰϳ;ϳͿ͗ϲϵϮͲϱ͘ Ϯϵ͘dĂƐĂŶD͕DƵƐƐŽ'͕,ĂŽd͕sŝĚĂůD͕DĂĐZĂĞ ͕ ZŽƚŚ &W͘ ^ĞůĞĐƟŶŐ ĐĂƵƐĂů ŐĞŶĞƐ ĨƌŽŵ ŐĞŶŽŵĞͲǁŝĚĞ ĂƐƐŽĐŝĂƟŽŶ ƐƚƵĚŝĞƐ ǀŝĂ ĨƵŶĐƟŽŶĂůůLJ ĐŽŚĞƌĞŶƚ ƐƵďŶĞƚǁŽƌŬƐ͘ EĂƚƵƌĞŵĞƚŚŽĚƐϮϬϭϱ͖ϭϮ;ϮͿ͗ϭϱϰͲϵ͘ ϯϬ͘ůďĞƌƚ&t͕<ƌƵŐůLJĂŬ>͘dŚĞƌŽůĞŽĨƌĞŐƵůĂƚŽƌLJ ǀĂƌŝĂƟŽŶ ŝŶ ĐŽŵƉůĞdž ƚƌĂŝƚƐ ĂŶĚ ĚŝƐĞĂƐĞ͘ EĂƚƵƌĞƌĞǀŝĞǁƐ'ĞŶĞƟĐƐϮϬϭϱ͖ϭϲ;ϰͿ͗ϭϵϳͲ 212.

31. de Leeuw CA, Neale BM, Heskes T, Posthuma ͘ dŚĞ ƐƚĂƟƐƟĐĂů ƉƌŽƉĞƌƟĞƐ ŽĨ ŐĞŶĞͲƐĞƚ analysis. EĂƚƵƌĞ ƌĞǀŝĞǁƐ 'ĞŶĞƟĐƐ ϮϬϭϲ͖ 17(6): 353-64.

32. de Leeuw CA, Mooij JM, Heskes T, Posthuma ͘D'D͗ŐĞŶĞƌĂůŝnjĞĚŐĞŶĞͲƐĞƚĂŶĂůLJƐŝƐ ŽĨ't^ĚĂƚĂ͘W>Ž^ĐŽŵƉƵƚĂƟŽŶĂůďŝŽůŽŐLJ ϮϬϭϱ͖ϭϭ;ϰͿ͗ĞϭϬϬϰϮϭϵ͘

ϯϯ͘ZŝƚĐŚŝĞD͕,ŽůnjŝŶŐĞƌZ͕>ŝZ͕WĞŶĚĞƌŐƌĂƐƐ ^͕ <ŝŵ ͘ DĞƚŚŽĚƐ ŽĨ ŝŶƚĞŐƌĂƟŶŐ data to uncover genotype-phenotype ŝŶƚĞƌĂĐƟŽŶƐ͘ EĂƚƵƌĞ ƌĞǀŝĞǁƐ 'ĞŶĞƟĐƐ ϮϬϭϱ͖ϭϲ;ϮͿ͗ϴϱͲϵϳ͘

ϯϰ͘EŽǀĂƌŝŶŽ '͕&ĞŶƐƚĞƌŵĂŬĞƌ'͕ĂŬŝ D^͕Ğƚ Ăů͘ džŽŵĞ ƐĞƋƵĞŶĐŝŶŐ ůŝŶŬƐ ĐŽƌƟĐŽƐƉŝŶĂů motor neuron disease to common ŶĞƵƌŽĚĞŐĞŶĞƌĂƟǀĞ ĚŝƐŽƌĚĞƌƐ͘ Science

;EĞǁzŽƌŬ͕EzͿϮϬϭϰ͖ϯϰϯ;ϲϭϳϬͿ͗ϱϬϲͲϭϭ͘

7

ĞŶǀŝƌŽŶŵĞŶƚĂů ŶĞƚǁŽƌŬ ĂƐƐŽĐŝĂƟŽŶƐ͘

ŝŽŝŶĨŽƌŵĂƟĐƐ ;KdžĨŽƌĚ͕ ŶŐůĂŶĚͿ ϮϬϭϰ͖

30(5): 698-705.

ϯϴ͘ DĂŶŬŽŽ W<͕ ^ŚĞŶ Z͕ ^ĐŚƵůƚnj E͕ >ĞǀŝŶĞ ͕ Sander C. Time to recurrence and survival in serous ovarian tumors predicted from ŝŶƚĞŐƌĂƚĞĚ ŐĞŶŽŵŝĐ ƉƌŽĮůĞƐ͘ PloS one ϮϬϭϭ͖ϲ;ϭϭͿ͗ĞϮϰϳϬϵ͘

ϯϵ͘ŬĂǀŝĂh͕>ŝƚǀŝŶK͕<ŝŵ:͕ĞƚĂů͘ŶŝŶƚĞŐƌĂƚĞĚ approach to uncover drivers of cancer. Cell ϮϬϭϬ͖ϭϰϯ;ϲͿ͗ϭϬϬϱͲϭϳ͘

40. Cirulli ET, Lasseigne BN, Petrovski S, et Ăů͘ džŽŵĞ ƐĞƋƵĞŶĐŝŶŐ ŝŶ ĂŵLJŽƚƌŽƉŚŝĐ ůĂƚĞƌĂů ƐĐůĞƌŽƐŝƐ ŝĚĞŶƟĮĞƐ ƌŝƐŬ ŐĞŶĞƐ ĂŶĚ pathways. ^ĐŝĞŶĐĞ ;EĞǁ zŽƌŬ͕ EzͿ ϮϬϭϱ͖ 347(6229): 1436-41. ϰϭ͘ WƵƌĐĞůů ^D͕ DŽƌĂŶ :>͕ &ƌŽŵĞƌ D͕ Ğƚ Ăů͘  ƉŽůLJŐĞŶŝĐ ďƵƌĚĞŶ ŽĨ ƌĂƌĞ ĚŝƐƌƵƉƟǀĞ ŵƵƚĂƟŽŶƐŝŶƐĐŚŝnjŽƉŚƌĞŶŝĂ͘NatureϮϬϭϰ͖ 506(7487): 185-90. ϰϮ͘ ^ŝŶŐůĞƚŽŶ ͕ ,ĂƌĚLJ :͘ dŚĞ ǀŽůƵƟŽŶ ŽĨ 'ĞŶĞƟĐƐ͗ ůnjŚĞŝŵĞƌ͛Ɛ ĂŶĚ WĂƌŬŝŶƐŽŶ͛Ɛ Diseases. NeuronϮϬϭϲ͖ϵϬ;ϲͿ͗ϭϭϱϰͲϲϯ͘ ϰϯ͘ <ƵůĞƐŚŽǀ s͕ yŝĞ ͕ ŚĞŶ Z͕ Ğƚ Ăů͘ tŚŽůĞͲ

genome haplotyping using long reads and ƐƚĂƟƐƟĐĂůŵĞƚŚŽĚƐ͘Nature biotechnology ϮϬϭϰ͖ϯϮ;ϯͿ͗ϮϲϭͲϲ͘

ϰϰ͘ 'ĂǁĂĚ ͕ <ŽŚ t͕ YƵĂŬĞ ^Z͘ ^ŝŶŐůĞͲĐĞůů genome sequencing: current state of the science. EĂƚƵƌĞ ƌĞǀŝĞǁƐ 'ĞŶĞƟĐƐ ϮϬϭϲ͖ 17(3): 175-88.

ϰϱ͘ DĐŽŶŶĞůů D:͕ >ŝŶĚďĞƌŐ DZ͕ ƌĞŶŶĂŶĚ <:͕ Ğƚ Ăů͘ DŽƐĂŝĐ ĐŽƉLJ ŶƵŵďĞƌ ǀĂƌŝĂƟŽŶ ŝŶ human neurons. ^ĐŝĞŶĐĞ ;EĞǁ zŽƌŬ͕ EzͿ ϮϬϭϯ͖ϯϰϮ;ϲϭϱϴͿ͗ϲϯϮͲϳ͘ ϰϲ͘ &ĞƵŬ >͕ ĂƌƐŽŶ Z͕ ^ĐŚĞƌĞƌ ^t͘ ^ƚƌƵĐƚƵƌĂů ǀĂƌŝĂƟŽŶ ŝŶ ƚŚĞ ŚƵŵĂŶ ŐĞŶŽŵĞ͘ Nature ƌĞǀŝĞǁƐ'ĞŶĞƟĐƐϮϬϬϲ͖ϳ;ϮͿ͗ϴϱͲϵϳ͘ ϰϳ͘ 'ƵĂŶ W͕ ^ƵŶŐ t<͘ ^ƚƌƵĐƚƵƌĂů ǀĂƌŝĂƟŽŶ ĚĞƚĞĐƟŽŶ ƵƐŝŶŐ ŶĞdžƚͲŐĞŶĞƌĂƟŽŶ ƐĞƋƵĞŶĐŝŶŐĚĂƚĂ͗ĐŽŵƉĂƌĂƟǀĞƚĞĐŚŶŝĐĂů review. DĞƚŚŽĚƐ ;^ĂŶ ŝĞŐŽ͕ ĂůŝĨͿ ϮϬϭϲ͖ 102: 36-49. ϰϴ͘ tĞŝƐĐŚĞŶĨĞůĚƚ :͕ ^LJŵŵŽŶƐ K͕ ^Ɖŝƚnj &͕ <ŽƌďĞů:K͘WŚĞŶŽƚLJƉŝĐŝŵƉĂĐƚŽĨŐĞŶŽŵŝĐ ƐƚƌƵĐƚƵƌĂůǀĂƌŝĂƟŽŶ͗ŝŶƐŝŐŚƚƐĨƌŽŵĂŶĚĨŽƌ human disease. EĂƚƵƌĞ ƌĞǀŝĞǁƐ 'ĞŶĞƟĐƐ ϮϬϭϯ͖ϭϰ;ϮͿ͗ϭϮϱͲϯϴ͘

ϰϵ͘dŽŌD͕ZŽƐƐK͘ŽƉLJŶƵŵďĞƌǀĂƌŝĂƟŽŶŝŶ Parkinson’s disease. 'ĞŶŽŵĞ DĞĚŝĐŝŶĞ ϮϬϭϬ͖Ϯ;ϵͿ͗ϲϮ͘

ϱϬ͘tĂŶŐz͕zĂŶŐY͕tĂŶŐ͘dŚĞĞǀŽůƵƟŽŶŽĨ nanopore sequencing. &ƌŽŶƟĞƌƐŝŶŐĞŶĞƟĐƐ ϮϬϭϰ͖ϱ͗ϰϰϵ͘

ϱϭ͘ ZŚŽĂĚƐ ͕ Ƶ <&͘ WĂĐŝŽ ^ĞƋƵĞŶĐŝŶŐ ĂŶĚ /ƚƐ ƉƉůŝĐĂƟŽŶƐ͘ Genomics, proteomics &

ďŝŽŝŶĨŽƌŵĂƟĐƐϮϬϭϱ͖ϭϯ;ϱͿ͗ϮϳϴͲϴϵ͘

ϱϮ͘ EŐ ^͕ dƵƌŶĞƌ ,͕ ZŽďĞƌƚƐŽŶ W͕ Ğƚ Ăů͘ Targeted capture and massively parallel ƐĞƋƵĞŶĐŝŶŐŽĨϭϮŚƵŵĂŶĞdžŽŵĞƐ͘Nature ϮϬϬϵ͖ϰϲϭ;ϳϮϲϭͿ͗ϮϳϮͲϲ͘

ϱϯ͘ ^ŽůĚŶĞƌ &͕ ^ƚĞůnjĞƌ z͕ ^ŚŝǀĂůŝůĂ ^͕ Ğƚ Ăů͘ Parkinson-associated risk variant in distal enhancer of alpha-synuclein modulates ƚĂƌŐĞƚ ŐĞŶĞ ĞdžƉƌĞƐƐŝŽŶ͘ Nature ϮϬϭϲ͖ 533(7601): 95-9.

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W>Ž^ŐĞŶĞƟĐƐϮϬϭϯ͖ϵ;ϵͿ͗ĞϭϬϬϯϳϮϯ͘

ϱϴ͘ 'ŽŶnjĂůĞnjͲWĞŶĂƐ :͕ ŵŝŐŽ :͕ ^ĂŶƚŽŵĞ >͕ Ğƚ al. Targeted resequencing of regulatory ƌĞŐŝŽŶƐ Ăƚ ƐĐŚŝnjŽƉŚƌĞŶŝĂ ƌŝƐŬ ůŽĐŝ͗ ZŽůĞ ŽĨ ƌĂƌĞ ĨƵŶĐƟŽŶĂů ǀĂƌŝĂŶƚƐ Ăƚ ĐŚƌŽŵĂƟŶ repressive states. Schizophrenia research ϮϬϭϲ͖ϭϳϰ;ϭͲϯͿ͗ϭϬͲϲ͘

ϱϵ͘ ĞŝůŝŶĂ ͕ ZƵĚĞŶŬŽ /E͕ <ĂŐĂŶŽǀŝĐŚ ͕ Ğƚ Ăů͘ hŶďŝĂƐĞĚ ƐĐƌĞĞŶ ĨŽƌ ŝŶƚĞƌĂĐƚŽƌƐ ŽĨ leucine-rich repeat kinase 2 supports a common pathway for sporadic and

familial Parkinson disease. WƌŽĐĞĞĚŝŶŐƐŽĨ

ƚŚĞ EĂƟŽŶĂů ĐĂĚĞŵLJ ŽĨ ^ĐŝĞŶĐĞƐ ŽĨ ƚŚĞ hŶŝƚĞĚ ^ƚĂƚĞƐ ŽĨ ŵĞƌŝĐĂ ϮϬϭϰ͖ ϭϭϭ;ϳͿ͗

2626-31.

60. Yamanaka S. Induced pluripotent stem cells: past, present, and future. Cell stem cell ϮϬϭϮ͖ϭϬ;ϲͿ͗ϲϳϴͲϴϰ͘