Imperial College London

Dr Nicky Whiffin

Faculty of MedicineNational Heart & Lung Institute








Hammersmith HospitalHammersmith Campus






BibTex format

author = {Whiffin, N and Armean, IM and Kleinman, A and Marshall, JL and Minikel, EV and Goodrich, JK and Quaife, NM and Cole, JB and Wang, Q and Karczewski, KJ and Cummings, BB and Francioli, L and Laricchia, K and Guan, A and Alipanahi, B and Morrison, P and Baptista, MAS and Merchant, KM and Genome, Aggregation Database Production Team and Genome, Aggregation Database Consortium and Ware, JS and Havulinna, AS and Iliadou, B and Lee, J-J and Nadkarni, GN and Whiteman, C and 23andMe, Research Team and Daly, M and Esko, T and Hultman, C and Loos, RJF and Milani, L and Palotie, A and Pato, C and Pato, M and Saleheen, D and Sullivan, PF and Alföldi, J and Cannon, P and MacArthur, DG},
doi = {10.1038/s41591-020-0893-5},
journal = {Nature Medicine},
pages = {869--877},
title = {The effect of LRRK2 loss-of-function variants in humans.},
url = {},
volume = {26},
year = {2020}

RIS format (EndNote, RefMan)

AB - Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson's disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns5-8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9, 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work10, confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.
AU - Whiffin,N
AU - Armean,IM
AU - Kleinman,A
AU - Marshall,JL
AU - Minikel,EV
AU - Goodrich,JK
AU - Quaife,NM
AU - Cole,JB
AU - Wang,Q
AU - Karczewski,KJ
AU - Cummings,BB
AU - Francioli,L
AU - Laricchia,K
AU - Guan,A
AU - Alipanahi,B
AU - Morrison,P
AU - Baptista,MAS
AU - Merchant,KM
AU - Genome,Aggregation Database Production Team
AU - Genome,Aggregation Database Consortium
AU - Ware,JS
AU - Havulinna,AS
AU - Iliadou,B
AU - Lee,J-J
AU - Nadkarni,GN
AU - Whiteman,C
AU - 23andMe,Research Team
AU - Daly,M
AU - Esko,T
AU - Hultman,C
AU - Loos,RJF
AU - Milani,L
AU - Palotie,A
AU - Pato,C
AU - Pato,M
AU - Saleheen,D
AU - Sullivan,PF
AU - Alföldi,J
AU - Cannon,P
AU - MacArthur,DG
DO - 10.1038/s41591-020-0893-5
EP - 877
PY - 2020///
SN - 1078-8956
SP - 869
TI - The effect of LRRK2 loss-of-function variants in humans.
T2 - Nature Medicine
UR -
UR -
UR -
UR -
VL - 26
ER -