SnapShot: Genetics of Parkinson’s Disease José Brás, Rita Guerreiro, and John Hardy Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 1PJ, UK

Disease-linked expression

LRRK2 PLA2G6 SNCA PINK1 FBX07 DJ-1 VPS35 DNAJC6 PARK2 ATP13A2 SYNJ1

LRRK2

Medium risk

GBA

SNCA, LRRK2, MAPT, RAB7L1, BST1, HLA-DRB5, GAK, ACMSD, STK39, MCCC1, SYT11, CCDC62, FGF20, STX1B, GPNMB, SIPA1L2, INPP5F, MIR4697HG, GCH1, VPS13C, SCARB2, RIT2, DDRGK1, SREBF1

Low risk

Average risk

Pleomorphic risk: SNCA

High risk

Effect size/risk of disease

Disease-causing

Genetic landscape of Parkinson’s Disease

Locus triplications

Locus duplications

k/ ris nts ing aria d v co n- tive Average expression No tec o r p

Very rare Very common Variant frequency in the general population

gene official symbol

gene name

Missense causative mutations: A30P, E46K, H50Q, G51D, A53T

Risk location

Possible pathways / pathological biological processes

mendelIAn genes SNCA

Synuclein, alpha

4q21

Synaptic function; mitochondrial function; autophagy/lysosomal degradation

PARK2

Parkin RBR E3 ubiquitin protein ligase

6q25.2-q27

Mitochondrial function/mitophagy; ubiquitination; synaptic function

PINK1

PTEN -induced putative kinase 1

1p36

Mitochondrial function/mitophagy

PARK7/DJ-1

Parkinson protein 7

1p36.23

Inflammation/immune system; mitochondrial function

LRRK2

Leucine-rich repeat kinase 2

12q12

Synaptic function; inflammation/immune system; autophagy/lysosomal degradation

PLA2G6

Phospholipase A2, group VI

22q13.1

Mitochondrial function

FBXO7

F-box protein 7

22q12.3

Ubiquitination; mitochondrial function/mitophagy

VPS35

Vacuolar protein sorting 35 homolog (S. cerevisiae)

16q12

Autophagy/lysosomal degradation; endocytosis

ATP13A2

ATPase type 13A2

1p36

Mitochondrial function; autophagy/lysosomal degradation

DNAJC6

DnaJ (Hsp40) homolog, subfamily C, member 6

1p31.3

Synaptic function; endocytosis

SYNJ1

Synaptojanin 1

21q22.2

Synaptic function; endocytosis

RIsk genes GBA

Glucosidase, beta, acid

1q21

Inflammation/immune system; autophagy/lysosomal degradation; metabolic pathways

RIsk locI MAPT

Microtubule-associated protein tau

17q21.1

Microtubule stabilization and axonal transport

RAB7L1

RAB7, member RAS oncogene family-like 1

1q32

Autophagy/lysosomal degradation

BST1

Bone marrow stromal cell antigen 1

4p15

Immune system

HLA-DRB5

Major histocompatibility complex, class II, DR beta 5

6p21.3

Inflammation/immune system

GAK/

Cyclin-G-associated kinase

4p16

Autophagy/lysosomal degradation; synaptic function; endocytosis

ACMSD

Aminocarboxymuconate semialdehyde decarboxylase

2q21.3

Tryptophan metabolism; metal ion binding; metabolic pathways

STK39

Serine threonine kinase 39

2q24.3

Inflammation/immune system; protein kinase binding; cellular stress response

SYT11

Synaptotagmin XI

1q21.2

Synaptic function; transporter activity; metal ion binding; substrate for PARK2

FGF20

Fibroblast growth factor 20

8p22

Growth factor activity; FGF receptor binding

STX1B

Syntaxin 1B

16p11.2

Synaptic function; SNAP receptor activity; protein domain-specific binding

GPNMB

Glycoprotein (transmembrane) nmb

7p15

Integrin binding; heparin binding; cancer pathways

SIPA1L2

Signal-induced proliferation-associated 1 like 2

1q42.2

GTPase activator activity

INPP5F

Inositol polyphosphate-5-phosphatase F

10q26.11

Phosphoric ester hydrolase activity

MIR4697HG

MIR4697 host gene (non-protein coding)

11q25

GCH1

GTP cyclohydrolase 1

14q22.1-q22.2

GTP binding; calcium ion binding; BH4 metab; metabolic pathways

VPS13C

Vacuolar protein sorting 13 homolog C (S. cerevisiae)

15q22.2

Endocytosis

DDRGK1

DDRGK domain containing 1

20p13

Protein binding

MCCC1

Methylcrotonoyl-CoA carboxylase 1 (alpha)

3q27

Biotin carboxylase activity; methylcrotonoyl-CoA carboxylase activity; metabolic pathways

SCARB2

Scavenger receptor class B, member 2

4q21.1

Autophagy/lysosomal degradation; receptor activity (lysosomal receptor for GBA targeting); enzyme binding

CCDC62

Coiled-coil domain containing 62

12q24.31

Nuclear receptor coactivator; cancer pathways

RIT2

Ras-like without CAAX 2

18q12.3

Synaptic function; calmodulin binding; GTP binding

SREBF1

Sterol regulatory element binding transcription factor 1

17p11.2

Chromatin binding; cholesterol and steroid metabolic processes

570

Cell 160, January 29, 2015 ©2015 Elsevier Inc.

DOI http://dx.doi.org/10.1016/j.cell.2015.01.019

See online version for legend and references.

SnapShot: Genetics of Parkinson’s Disease José Brás, Rita Guerreiro, and John Hardy Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 1PJ, UK Different types of genetic technologies and approaches allow for the study and identification of different types of genetic variability in a disease. Here, represented are the genes and genetic loci independently replicated as being associated with the development of Parkinson’s disease (PD)/parkinsonism. Genetic analyses of familial cases (mainly genetic linkage [blue area] and, more recently, exome sequencing [green area]) have led to the identification of causative mutations in 11 genes implicated in monogenic typical or atypical forms of parkinsonism. From these, eight genes have been associated with autosomal-recessive patterns of inheritance, either causing typical early-onset PD (PARK2, PINK1, and DJ-1/PARK7) or atypical forms of parkinsonism with juvenile onsets (ATP13A2, PLA2G6, FBXO7, DNAJC6, and SYNJ1). Three genes have been shown to cause typical autosomal dominant PD phenotypes (SNCA, LRRK2, and VPS35) associated with early- or late-onsets of disease. Additionally, other genes are known to harbor mutations associated with non-PD disorders that may present with parkinsonism, for example ATXN2, ATXN3, GCH1, GRN, MAPT, C9ORF72, CSF1R, TH, and SPG1. Very recently, mutations in RAB39B have been described as causing X-linked intellectual disability plus a phenotype indistinguishable from early-onset PD. Other chromosomal loci (like PARK3 and PARK10, for example) have been identified by genome-wide approaches as genomic regions associated with typical PD. These loci may contain other, still-to-be-identified, PD genes. Lastly, there are also some genes that have been suggested to harbor causative PD mutations, which have not been confirmed: GIGYF2, HTRA2, UCHL1, EIF4G1, and SPR. By using genetic family studies (for LRRK2) and a candidate gene approach (for GBA), high-risk variants (with odds ratio in the range of 5–8) for the development of typical PD have been identified in both genes (central part of the graph). More recently, the development of whole-genome genotyping platforms (pink area of the graph) has allowed for the study of the involvement of common variants with low risk in the disease. This has led to the identification of 24 new genetic loci by several independent genome-wide association studies (GWAS) and meta-analyses: SNCA, LRRK2, MAPT, RAB7L1, BST1, HLA-DRB5, GAK, ACMSD, STK39, MCCC1, SYT11, CCDC62, FGF20, STX1B, GPNMB, SIPA1L2, INPP5F, MIR4697HG, GCH1, VPS13C, SCARB2, RIT2, DDRGK1, and SREBF1. Because of the way these studies are designed, they only identify genetic regions associated with disease and not specific genes or variants. For this reason, if the significant single nucleotide polymorphisms (SNPs) are intergenic or the region contains more than one gene, the locus usually gets its name from the gene closest to the significant hit. Very few of these significant hits have a clear functional role in the disease and, because of this, follow-up work is currently underway to determine exactly which genes and genetic variants are important for the disease and how they are exerting their effect. Recently, an unbiased screen for interactors of LRRK2 identified the most likely candidates for two of these GWAS loci: in chromosome 1q32, the associated locus (originally named RAB7L1/NUCKS1) contained five genes, and in chromosome 4p16, the associated locus (originally named GAK/TMEM175/DGKQ) contained nearly ten genes. RAB7L1 and GAK have now been identified as LRRK2 interactors and, in this way, as the most likely hits in each region. Additionally, these proteins were shown to form a newly identified protein complex that promotes clearance of Golgi-derived vesicles via the autophagy-lysosome system both in vitro and in vivo, clearly highlighting the role the “Autophagy/Lysosomal degradation” pathway in Parkinson’s disease. More generally, pathway analyses of GWAS data implicated other biological processes as primary etiological events in the disease with significant overrepresentation of association signals in pathways related to “regulation of leucocyte/lymphocyte activity,” “cytokine-mediated signaling,” “axonal guidance,” “focal adhesion,” and “calcium signaling.” Representation of genes within each group in the graph is approximate and does not reflect differences in frequency or risk. Pleomorphic Risk—Exemplified by SNCA This panel illustrates that, at the same locus, several disease-related genetic mechanisms may co-exist, each influencing disease through different biological effects on a single gene. In this particular model, expression of a gene is positively correlated with risk shown by duplication mutations causing Parkinson’s disease. Five coding mutations have been identified as the cause of disease in early-onset familial cases. Duplications and triplications of the SNCA locus have also been implicated as the cause of early-onset Parkinson’s disease. Interestingly, GWAS have also identified two different association signals in this locus, representing common variability with a low effect in the disease. Possible protective variants are also represented in the graph. Acknowledgments Research studies in the authors’ lab are mainly supported by Alzheimer’s Research UK (ARUK), including a Fellowship to R.G.; by a Fellowship from Alzheimer’s Society to J.B.; by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson’s Disease Consortium, whose members are from the UCL/Institute of Neurology, the University of Sheffield, and the MRC Protein Phosphorylation Unit at the University of Dundee; and by an anonymous donor. References Beilina, A., Rudenko, I.N., Kaganovich, A., Civiero, L., Chau, H., Kalia, S.K., Kalia, L.V., Lobbestael, E., Chia, R., Ndukwe, K., et al.; International Parkinson’s Disease Genomics Consortium; North American Brain Expression Consortium (2014). Proc. Natl. Acad. Sci. USA 111, 2626–2631. Bras, J., Guerreiro, R., and Hardy, J. (2012). Nat. Rev. Neurosci. 13, 453–464. Edwards, Y.J., Beecham, G.W., Scott, W.K., Khuri, S., Bademci, G., Tekin, D., Martin, E.R., Jiang, Z., Mash, D.C., ffrench-Mullen, J., et al. (2011). PLoS ONE 6, e16917. Holmans, P., Moskvina, V., Jones, L., Sharma, M., Vedernikov, A., Buchel, F., Saad, M., Bras, J.M., Bettella, F., Nicolaou, N., et al.; International Parkinson’s Disease Genomics Consortium (2013). Hum. Mol. Genet. 22, 1039–1049. Manolio, T.A., Collins, F.S., Cox, N.J., Goldstein, D.B., Hindorff, L.A., Hunter, D.J., McCarthy, M.I., Ramos, E.M., Cardon, L.R., Chakravarti, A., et al. (2009). Nature 461, 747–753. Manzoni, C., and Lewis, P.A. (2013). FASEB J. 27, 3424–3429. Nalls, M. Pankratz, N., Lill, C.M., Do, C.B., Hernandez, D.G., Saad, M., DeStefano, A.L., Kara, E., Bras, J., Sharma, M., et al. (2014). Nat. Gen. 46, 989–993. Singleton, A., and Hardy, J. (2011). Hum. Mol. Genet. 20 (R2), R158–R162.

570.e1 Cell 160, January 29, 2015 ©2015 Elsevier Inc.  DOI http://dx.doi.org/10.1016/j.cell.2015.01.019