Genetic Analysis of Pathways to Parkinson Disease
Authors: John Hardy
Journal: Neuron (2010)

In this review I outline the arguments as to whether we should consider Parkinson disease one or more than one entity and discuss genetic findings from Mendelian and whole-genome association analysis in that context. I discuss what the demonstration of disease spread implies for our analysis of the genetic and epidemiologic risk factors for disease and outline the surprising fact that we now have genetically identified on the order of half our risk for developing the disease. In this review I outline the arguments as to whether we should consider Parkinson disease one or more than one entity and discuss genetic findings from Mendelian and whole-genome association analysis in that context. I discuss what the demonstration of disease spread implies for our analysis of the genetic and epidemiologic risk factors for disease and outline the surprising fact that we now have genetically identified on the order of half our risk for developing the disease. We have two goals in the genetic analysis of disease: the first is to increase the accuracy of risk prediction, with an intention of getting better at diagnosing the disease earlier and perhaps targeting presymptomatic therapy; the second is to define the pathways that lead to cell death so that we can design approaches that intervene in those pathways and act as mechanistic therapies. In Parkinson disease, a neurodegenerative disorder affecting movement and usually characterized by the presence of α-synuclein containing Lewy bodies in damaged neurons, genetic analysis has been remarkably successful, with many mendelian loci already described, a common high-risk variant identified and many common low-risk variants recently elucidated. This is particularly remarkable because epidemiologic investigations preceding the identification of the α-synuclein (SNCA) locus consistently suggested that genes were unimportant in disease etiology. As our knowledge of the disease has increased over the last 15 years, the proportion of risk assigned to the environment has consistently decreased and, while associations with environmental factors have been confirmed (such as that showing a negative association with smoking), no environmental risk factor with a convincing pathogenic role in the disease has yet been described. We and others have recently comprehensively reviewed the identification of mendelian genes for Parkinson disease (Hardy et al., 2009Hardy J. Lewis P. Revesz T. Lees A. Paisan-Ruiz C. The genetics of Parkinson's syndromes: A critical review.Curr. Opin. Genet. Dev. 2009; 19: 254-265Crossref PubMed Scopus (173) Google Scholar, Klein and Lohmann-Hedrich, 2007Klein C. Lohmann-Hedrich K. Impact of recent genetic findings in Parkinson's disease.Curr. Opin. Neurol. 2007; 20: 453-464Crossref PubMed Scopus (92) Google Scholar, Cookson and Bandmann, 2010Cookson M.R. Bandmann O. Parkinson's disease: Insights from pathways.Hum. Mol. Genet. 2010; 19: R21-R27Crossref PubMed Scopus (134) Google Scholar). Given this, my purpose in this review is to discuss four issues:1.To discuss whether all the identified genes relate to single entity and what pathways have been identified as relevant to disease.2.To discuss how the identification of risk loci through genome-wide association studies relate to the Mendelian genes and whether we should inevitably expect those low-risk loci to encode proteins that map onto the same pathways as those identified through the identification of Mendelian loci:3.To discuss the implication of permissive templating ("prionoid") behavior of α-synuclein to the concept of disease risk4.To discuss the proportion of risk for disease that has been identified so far. Table 1 lists the loci at which pathogenic mutations lead to parkinsonism (for references, see Hardy et al., 2009Hardy J. Lewis P. Revesz T. Lees A. Paisan-Ruiz C. The genetics of Parkinson's syndromes: A critical review.Curr. Opin. Genet. Dev. 2009; 19: 254-265Crossref PubMed Scopus (173) Google Scholar). These include those loci traditionally noted as "Parkinson loci" as well as others that are not, including MAPT, SCA2, SCA3, and spastacsin, which can clinically present as Parkinson disease but often is clinically distinct. In some diseases, most clearly Alzheimer disease, the disease is defined by its pathology. In Parkinson disease, the disease has been traditionally defined clinically, but the vast majority of cases of disease have the pathology of Lewy bodies (Hughes et al., 1993Hughes A.J. Daniel S.E. Blankson S. Lees A.J. A clinicopathologic study of 100 cases of Parkinson's disease.Arch. Neurol. 1993; 50: 140-148Crossref PubMed Scopus (843) Google Scholar). However, while the vast majority of idiopathic cases have Lewy bodies, the genetic forms of the disease have variable pathologies (Table 1). Thus part of my intention in this review is to question how we should group the genetic loci if we are trying to understand the pathogenesis of the disorder. Should we use clinical criteria (in which case, all of the loci may stake a claim as to involvement), or should we use pathological criteria, in which case the number clearly involved is much smaller although for many, the pathology has not been documented?Table 1Mendelian Genes that Lead to Parkinsonism and Their PathologyLocusGenesClinical FeaturesPathologyDominantPARK1/4α-SynucleinTypical PD but can sometimes have a dementia presentationLewy bodiesPARK8LRRK2Typical PDUsually Lewy bodies: sometime tangles, sometimes neitherFTDP-17MAPTMost mutations have a dementia phenotype but some have a typical PD presentationTau/tangle pathologySCA3Ataxin3Usually ataxia in Europeans, but often Parkinsonian especially in AfricansProbably not Lewy bodies. Probably polyglutamine inclusionsSCA2Ataxin2Usually ataxia in Europeans, but often Parkinsonian especially in AsiansProbably not Lewy bodies. Probably polyglutamine inclusionsRecessivePARK2ParkinVery slowly progressive early onset disease usually with sleep benefitUsually not Lewy bodiesPARK6PINK1Usually very slowly progressive early onset disease usually with sleep benefitOne case with Lewy bodiesPARK7DJ-1Little data, but seems similar to parkinNot knownPARK9ATP13A2Aggressive and complex parkinsonism with many additional featuresNot knownPARK14PLA2G6Aggressive and complex parkinsonism with many additional featuresLewy bodiesSPG11SpatacsinUsually spastic paraplegia but sometimes aggressive and complex parkinsonism with additional featuresNot knownHigh-Risk LocusGaucher's (1) locusGBATypical PDLewy bodiesLow-Risk LociSNCATypical PDLewy bodiesMAPTLewy bodies (though tau pathology not systematically assessedLRRK2Typical PDLewy bodiesHLATypical PDLewy bodies Open table in a new tab The major argument in favor of using pathological criteria for the definition of disease is an analogy: in Alzheimer disease, the loci identified for the disorder, APP, and the presenilins clearly map into one pathway (Hardy and Selkoe, 2002Hardy J. Selkoe D.J. The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics.Science. 2002; 297: 353-356Crossref PubMed Scopus (11121) Google Scholar): defining the disease clinically would lead to confusion with a large series of other genes (MAPT, PRNP, PGRN, etc.) being grouped with them. A second argument is that both clinically and pathologically the disease seems to spread along neuronal pathway. This notion of the disease spreading has been most vividly captured by the work of Braak and colleagues (Braak et al., 2003Braak H. Del Tredici K. Rüb U. de Vos R.A. Jansen Steur E.N. Braak E. Staging of brain pathology related to sporadic Parkinson's disease.Neurobiol. Aging. 2003; 24: 197-211Abstract Full Text Full Text PDF PubMed Scopus (7336) Google Scholar) and is supported by the idea that misfolded synuclein acts as a template for other synuclein to deposit upon (see below). It is difficult to see how this templating pathogenesis could be relevant to those forms of the disease without Lewy body pathology. There are several arguments against using pathological criteria. First, the pathology of (for example) LRRK2 mutation carriers is variable with the majority of cases having Lewy bodies, but a minority have tangles and some having other pathology (Zimprich et al., 2004Zimprich A. Biskup S. Leitner P. Lichtner P. Farrer M. Lincoln S. Kachergus J. Hulihan M. Uitti R.J. Calne D.B. et al.Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.Neuron. 2004; 44: 601-607Abstract Full Text Full Text PDF PubMed Scopus (2318) Google Scholar). Second, a few compound heterozygote parkin mutation cases (e.g., Farrer et al., 2010Farrer M. Chan P. Chen R. Tan L. Lincoln S. Hernandez D. Forno L. Gwinn-Hardy K. Petrucelli L. Hussey J. et al.Lewy bodies and parkinsonism in families with parkin mutations.Ann. 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Third, although mutations in MAPT (microtubule-associated protein tau, or often referred to simply as tau) lead to a disorder that can closely clinically resemble idiopathic Parkinson disease, the majority have a dementing syndrome that is clearly different from Parkinson disease; however, the MAPT/tau haplotype shows an association with disease (see below) strongly suggesting that the pathogenic cascades in the tauopathies must be related to those in the synucleinopathies. A practical argument against using pathological criteria is that for many syndromes, we do not know the underlying pathology of many of the syndromes, and a lesson to be drawn from the case of LRRK2 mutations is that pathology can be variable. As Table 1 illustrates, there are many syndromes that can masquerade as Parkinson disease, some of which (e.g., SCA2 and SCA3) almost certainly have different pathogenic mechanisms since they are both polyglutamine repeat disorders. Furthermore, there are clear phenotypic differences between the diseases defined by their genetic etiology. As an example, the Japanese clinicians who first identified PARK2 encoded disease were clear that this was distinct from typical Parkinson disease, with a very prolonged and benign disease duration, profound dopamine sensitivity, and sleep benefit (Yamamura, 2010Yamamura Y. The long journey to the discovery of PARK2.Neuropathology. 2010; (in press. Published online July 27, 2010)https://doi.org/10.1111/j.1440-1789.2010.01144.xCrossref PubMed Scopus (8) Google Scholar); PINK1 and possibly (Bonifati et al., 2005Bonifati V. Rohé C.F. Breedveld G.J. Fabrizio E. De Mari M. Tassorelli C. Tavella A. Marconi R. Nicholl D.J. Chien H.F. et al.Italian Parkinson Genetics NetworkEarly-onset parkinsonism associated with PINK1 mutations: Frequency, genotypes, and phenotypes.Neurology. 2005; 65: 87-95Crossref PubMed Scopus (278) Google Scholar) DJ-1 and FBXO7 encoded diseases seem similar (Paisán-Ruiz et al., 2010Paisán-Ruiz C. Guevara R. Federoff M. Hanagasi H. Sina F. Elahi E. Schneider S.A. Schwingenschuh P. Bajaj N. Emre M. et al.Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations.Mov. Disord. 2010; 25: 1791-1800Crossref PubMed Scopus (186) Google Scholar). This is clearly clinically different from typical idiopathic Parkinson disease (see Hughes et al., 1993Hughes A.J. Daniel S.E. Blankson S. Lees A.J. A clinicopathologic study of 100 cases of Parkinson's disease.Arch. Neurol. 1993; 50: 140-148Crossref PubMed Scopus (843) Google Scholar) The pathway that has come most clearly out of the analysis of the Mendelian genes is a mitochondrial damage repair pathway. It is clear that parkin, an E3 ubiquitin ligase, and PINK1, a mitochondrial kinase, are genetically in the same pathway (with parkin downstream of PINK1) and that this pathway is involved in the elimination of damaged mitochondria (Park et al., 2006Park J. Lee S.B. Lee S. Kim Y. Song S. Kim S. Bae E. Kim J. Shong M. Kim J.M. Chung J. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin.Nature. 2006; 441: 1157-1161Crossref PubMed Scopus (1358) Google Scholar, Clark et al., 2006Clark I.E. Dodson M.W. Jiang C. Cao J.H. Huh J.R. Seol J.H. Yoo S.J. Hay B.A. Guo M. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin.Nature. 2006; 441: 1162-1166Crossref PubMed Scopus (1409) Google Scholar). DJ-1, and possibly FBX07, another ubiquitin ligase, are also likely to be involved in mitochondrial physiology. DJ-1 has been shown to translocate to the mitochondria and exert a protective effect on the application of oxidative stress (Canet-Avilés et al., 2004Canet-Avilés R.M. Wilson M.A. Miller D.W. Ahmad R. McLendon C. Bandyopadhyay S. Baptista M.J. Ringe D. Petsko G.A. Cookson M.R. The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization.Proc. Natl. Acad. Sci. USA. 2004; 101: 9103-9108Crossref PubMed Scopus (926) Google Scholar: see Cookson, 2010Cookson M.R. DJ-1, PINK1, and their effects on mitochondrial pathways.Mov. Disord. 2010; 25: S44-S48Crossref PubMed Scopus (41) Google Scholar). Whether the products of these genes are also directly involved in the same or different mitochondrial repair/elimination pathways is not yet clear. But the likelihood that all these genes map onto mitochondrial pathways and all have rather similar clinical phenotypes is striking (Paisán-Ruiz et al., 2010Paisán-Ruiz C. Guevara R. Federoff M. Hanagasi H. Sina F. Elahi E. Schneider S.A. Schwingenschuh P. Bajaj N. Emre M. et al.Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations.Mov. Disord. 2010; 25: 1791-1800Crossref PubMed Scopus (186) Google Scholar, Valente et al., 2004Valente E.M. Salvi S. Ialongo T. Marongiu R. Elia A.E. Caputo V. Romito L. Albanese A. Dallapiccola B. Bentivoglio A.R. PINK1 mutations are associated with sporadic early-onset parkinsonism.Ann. Neurol. 2004; 56: 336-341Crossref PubMed Scopus (423) Google Scholar, Yamamura, 2010Yamamura Y. The long journey to the discovery of PARK2.Neuropathology. 2010; (in press. Published online July 27, 2010)https://doi.org/10.1111/j.1440-1789.2010.01144.xCrossref PubMed Scopus (8) Google Scholar). It is notable that MPTP toxicity is also both dopamine selective and mitochondrial (Langston, 1989Langston J.W. Mechanisms underlying neuronal degeneration in Parkinson's disease: An experimental and theoretical treatise.Mov. Disord. 1989; 4: S15-S25Crossref PubMed Scopus (36) Google Scholar). Of course, MPTP selectivity is largely explicable through dopamine metabolism, but the clear impression is that dopamine and possibly other catecholamine neurons are selectively sensitive to mitochondrial damage (Schapira, 2008Schapira A.H. Mitochondria in the aetiology and pathogenesis of Parkinson's disease.Lancet Neurol. 2008; 7: 97-109Abstract Full Text Full Text PDF PubMed Scopus (683) Google Scholar, Dodson and Guo, 2007Dodson M.W. Guo M. Pink1, Parkin, DJ-1 and mitochondrial dysfunction in Parkinson's disease.Curr. Opin. Neurobiol. 2007; 17: 331-337Crossref PubMed Scopus (221) Google Scholar, Cookson and Bandmann, 2010Cookson M.R. Bandmann O. Parkinson's disease: Insights from pathways.Hum. Mol. Genet. 2010; 19: R21-R27Crossref PubMed Scopus (134) Google Scholar). A second pathway that is likely to be involved in Parkinson disease clearly involves the lysosomes. Glucosecerebrosidase and ATP13A2 are lysosomal enzymes (though the precise function of the latter is not yet clear). While there are interactions between lysosomal and mitochondrial metabolism (as there are between any cellular compartments), whether there is or should expected to be any close relationship between these loci and the mitochondrial loci is not clear. The two loci that all would agree are central to Parkinson disease, SNCA and LRRK2, are, in many ways, the most mysterious. α-synuclein clearly has a role in synaptic release (Cabin et al., 2002Cabin D.E. Shimazu K. Murphy D. Cole N.B. Gottschalk W. McIlwain K.L. Orrison B. Chen A. Ellis C.E. Paylor R. et al.Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein.J. Neurosci. 2002; 22: 8797-8807Crossref PubMed Google Scholar) and is related to the SNARE complex proteins (Burré et al., 2010Burré J. Sharma M. Tsetsenis T. Buchman V. Etherton M. Südhof T.C. {alpha}- synuclein promotes SNARE-complex assembly in vivo and in vitro.Science. 2010; (in press. Published online August 26, 2010)https://doi.org/10.1126/science.1195227Crossref PubMed Scopus (1239) Google Scholar), and, as a kinase, LRRK2 is almost certainly involved in signaling cascades (Dauer and Ho, 2010Dauer W. Ho C.C. The biology and pathology of the familial Parkinson's disease protein LRRK2.Mov. Disord. 2010; 25: S40-S43Crossref PubMed Scopus (22) Google Scholar), probably relating to cytoskeletal dynamics (MacLeod et al., 2006MacLeod D. Dowman J. Hammond R. Leete T. Inoue K. Abeliovich A. The familial Parkinsonism gene LRRK2 regulates neurite process morphology.Neuron. 2006; 52: 587-593Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar, Meixner et al., 2010Meixner A. Boldt K. Van Troys M. Askenazi M. Gloeckner C.J. Bauer M. Marto J.A. Ampe C. Kinkl N. Ueffing M. A QUICK screen for Lrrk2 interaction partners - leucine-rich repeat kinase 2 is involved in actin cytoskeleton dynamics.Mol. Cell. Proteomics. 2010; (in press. Published online September 27, 2010)https://doi.org/10.1074/mcp.M110.001172Crossref PubMed Scopus (94) Google Scholar). While there is some evidence that LRRK2 and SNCA may have a role in the same pathway (Lin et al., 2009Lin X. Parisiadou L. Gu X.L. Wang L. Shim H. Sun L. Xie C. Long C.X. Yang W.J. Ding J. et al.Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein.Neuron. 2009; 64: 807-827Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar), they do not appear to interact directly and their roles have no obvious connection to either lysosomal or mitochondrial metabolism. Genome-wide association studies (GWAS) have revolutionized our efforts to find loci at which common, normal genetic variability contributes to disease risk. Since these findings, for all diseases, are relatively new, we have little experience in conceptualizing what this common variability is and how it fits into the jigsaw of pathogenesis. In general, most of the loci found by this strategy are present in more than 5% of the population (allele frequencies of > 10%) and, if you have the risk allele, increase your risk of disease less than two fold over the population average (have odds ratios OR < 2). As a comparator, possessing a single APOE4 allele (present in 10% of the population) increases your risk of Alzheimer disease about four-fold. The majority of these low-risk loci for all diseases seem to mediate their effect by altering gene expression rather than through protein coding changes. In fact, there is an approximate relationship that as the odds ratios at a locus increases the more likely that the encoding gene will have a protein coding alteration at its heart (Singleton et al., 2010Singleton A.B. Hardy J. Traynor B.J. Houlden H. Towards a complete resolution of the genetic architecture of disease.Trends Genet. 2010; 26: 438-442Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). In Parkinson disease GWAS, the fact that the SNCA locus was the first to reach genome-wide significance is perhaps not surprising (Simón-Sánchez et al., 2009Simón-Sánchez J. Schulte C. Bras J.M. Sharma M. Gibbs J.R. Berg D. Paisan-Ruiz C. Lichtner P. Scholz S.W. Hernandez D.G. et al.Genome-wide association study reveals genetic risk underlying Parkinson's disease.Nat. Genet. 2009; 41: 1308-1312Crossref PubMed Scopus (1486) Google Scholar) (since it had previously been suggested on the basis of candidate gene analysis: Krüger et al., 1999Krüger R. Vieira-Saecker A.M. Kuhn W. Berg D. Müller T. Kühnl N. Fuchs G.A. Storch A. Hungs M. Woitalla D. et al.Increased susceptibility to sporadic Parkinson's disease by a certain combined α-synuclein/apolipoprotein E genotype.Ann. Neurol. 1999; 45: 611-617Crossref PubMed Scopus (252) Google Scholar) and this is consistent with the general suggestion that genetic variability at the loci encoding deposited protein influences the risk of disease (Singleton et al., 2004Singleton A. Myers A. Hardy J. The law of mass action applied to neurodegenerative disease: A hypothesis concerning the etiology and pathogenesis of complex diseases.Hum. Mol. Genet. 2004; 13: R123-R126Crossref PubMed Google Scholar). For instance, theMAPT locus is the most prominent locus for the tangle diseases and the prion locus the most prominent locus for Creutzfeldt-Jakob disease. Likewise, gene duplications at SNCA cause familial Parkinson disease: gene duplications at MAPT cause frontotemporal dementia and gene duplications at APP cause Alzheimer disease (for references, see Singleton et al., 2004Singleton A. Myers A. Hardy J. The law of mass action applied to neurodegenerative disease: A hypothesis concerning the etiology and pathogenesis of complex diseases.Hum. Mol. Genet. 2004; 13: R123-R126Crossref PubMed Google Scholar). In the case of the SNCA locus, it seems likely that those in the population who express about 10% more than the average have an increase of developing Parkinson disease increased by about 40% (Simón-Sánchez et al., 2009Simón-Sánchez J. Schulte C. Bras J.M. Sharma M. Gibbs J.R. Berg D. Paisan-Ruiz C. Lichtner P. Scholz S.W. Hernandez D.G. et al.Genome-wide association study reveals genetic risk underlying Parkinson's disease.Nat. Genet. 2009; 41: 1308-1312Crossref PubMed Scopus (1486) Google Scholar, Fuchs et al., 2008Fuchs J. Tichopad A. Golub Y. Munz M. Schweitzer K.J. Wolf B. Berg D. Mueller J.C. Gasser T. Genetic variability in the SNCA gene influences alpha-synuclein levels in the blood and brain.FASEB J. 2008; 22: 1327-1334Crossref PubMed Scopus (215) Google Scholar). While this finding is intellectually satisfying, it does not radically alter our view of the pathogenesis of disease, although it does make it genetically clear that α-synuclein is central to the pathogenesis in idiopathic disease. The fact that MAPT is the second locus to come out of the GWAS is more surprising, although it too had been previously identified as a candidate gene (Golbe et al., 2010Golbe L.I. Lazzarini A.M. Spychala J.R. Johnson W.G. Stenroos E.S. Mark M.H. Sage J.I. The tau A0 allele in Parkinson's disease.Mov. Disord. 2010; 16: 442-447Crossref Scopus (60) Google Scholar). While tau pathology is sometimes found in Parkinson disease, it is not pathognomic. Furthermore the haplotype that is associated with Parkinson disease is distinct from that associated with the tangle disorder, progressive supranuclear palsy (Vandrovcova et al., 2009Vandrovcova J. Pittman A.M. Malzer E. Abou-Sleiman P.M. Lees A.J. Wood N.W. de Silva R. Association of MAPT haplotype-tagging SNPs with sporadic Parkinson's disease.Neurobiol. Aging. 2009; 30: 1477-1482Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). Indeed, strictly, we cannot be sure that the association is with tau since the large haplotype that is associated with Parkinson disease has many other genes upon it (Fung et al., 2005Fung H.C. Evans J. Evans W. Duckworth J. Pittman A. de Silva R. Myers A. Hardy J. The architecture of the tau haplotype block in different ethnicities.Neurosci. Lett. 2005; 377: 81-84Crossref PubMed Scopus (12) Google Scholar). Finally, although we do not understand the relationship between the MAPT locus and Parkinson disease, it is worth remembering that while LRRK2 mutations usually give rise to α-synuclein pathology, they sometimes give rise to tangle pathology (Zimprich et al., 2004Zimprich A. Biskup S. Leitner P. Lichtner P. Farrer M. Lincoln S. Kachergus J. Hulihan M. Uitti R.J. Calne D.B. et al.Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.Neuron. 2004; 44: 601-607Abstract Full Text Full Text PDF PubMed Scopus (2318) Google Scholar) and that, while APP mutations usually give rise to tangle pathology, they sometimes give rise to Lewy body pathology (Hardy, 1994Hardy J. Lewy bodies in Alzheimer's disease in which the primary lesion is a mutation in the amyloid precursor protein.Neurosci. Lett. 1994; 180: 290-291Crossref PubMed Scopus (13) Google Scholar). In other words, there are at least three examples where there are genetic pathologic connections between α-synuclein and tau. The association between LRRK2 and sporadic disease seen in GWAS is not yet understood. It is not clear whether the association is driven by genetic variability in the expression of LRRK2 (which would imply that normal function of LRRK2 was important in disease etiology) or whether the effect is driven by some of the relatively common pathogenic mutations among the samples that have been used in the studies. LRRK2 is a very large gene and by no means had all of the samples used in the studies been sequenced. Thus, we cannot yet tell whether the LRRK2 finding in GWAS represents a new finding or a rediscovery of an old one. The identification of the HLA locus as reaching genome-wide significance is of great interest (Hamza et al., 2010Hamza T.H. Zabetian C.P. Tenesa A. Laederach A. Montimurro J. Yearout D. Kay D.M. Doheny K.F. Paschall J. Pugh E. et al.Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease.Nat. Genet. 2010; 42: 781-785Crossref PubMed Scopus (601) Google Scholar). It too had been previously identified as a candidate locus for Parkinson disease (Saiki et al., 2010Saiki M. Baker A. Williams-Gray C.H. Foltynie T. Goodman R.S. Taylor C.J. Compston D.A. Barker R.A. Sawcer S.J. Goris A. Association of the human leucocyte antigen region with susceptibility to Parkinson's disease.J. Neurol. Neurosurg. Psychiatry. 2010; 81: 890-891Crossref PubMed Scopus (48) Google Scholar), but its recognition as an important locus for disease has profound implications both narrowly for Parkinson disease and more generally for our interpretation of the identification of risk loci for late-onset neurodegenerative disease. Similar to the recent GWAS pointing to the complement cascade as contributing to risk of Alzheimer disease (Harold et al., 2009Harold D. Abraham R. Hollingworth P. Sims R. Gerrish A. Hamshere M.L. Pahwa J.S. Moskvina V. Dowzell K. Williams A. et al.Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.Nat. Genet. 2009; 41: 1088-1093Crossref PubMed Scopus (2190) Google Scholar, Lambert et al., 2009Lambert J.C. Heath S. Even G. Campion D. Sleegers K. Hiltunen M. Combarros O. Zelenika D. Bullido M.J. Tavernier B. et al.European Alzheimer's Disease Initiative InvestigatorsGenome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease.Nat. Genet. 2009; 41: 1094-1099Crossref PubMed Scopus (1154) Google Scholar) and the identification of complement H as the major risk locus for macular degeneration (Klein et al., 2005Klein R.J. Zeiss C. Chew E.Y. Tsai J.Y. Sackler R.S. Haynes C. Henning A.K. SanGiovanni J.P. Mane S.M. 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Inflammation, the complement system and the diseases of aging.Neurobiol. Aging. 2005; 26: 94-97Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar), though the precise role has not been clear. From these findings, one might propose that, given a pathogenic insult, at least some of these low-risk loci may not actually be important for disease etiology, either in triggering disease or disease progression or even in the pathways that initiate cell death, but rather are involved in the clearing out of the detritus. If this turns out to be the case, it is interesting to note that in the different diseases, different aspects of the immune system appear to play more or less important roles. Li and Kordower and their colleagues showed, in autopsy studies of patients with Parkinson disease who had, clinically successfully, received fetal dopmainergic grafts and survived more than 10 years had developed Lewy bodies in those grafts. This remarkable demonstration that grafted embryoni