Genome-Wide Analysis of the Parkinsonism-Dementia Complex

ORIGINAL CONTRIBUTION Genome-Wide Analysis of the Parkinsonism- Dementia Complex of Guam

Huw R. Morris, MB, PhD; John C. Steele, MD; Richard Crook, BSc; Fabienne Wavrant-De Vrièze, PhD; Luisa Onstead-Cardinale, BS; Katrina Gwinn-Hardy, MD; Nick W. Wood, MD, PhD; Matthew Farrer, PhD; Andrew J. Lees, MD; P. L. McGeer, MD, PhD; Teepu Siddique, MD, PhD; John Hardy, PhD; Jordi Perez-Tur, PhD

Background: Parkinsonism-dementia complex (PDC) went conventional linkage analysis in 5 families with PDC. is a neurofibrillary tangle degeneration involving the depo- One marker, D20S103, generated a logarithm of odds score sition of Alzheimer-type tau, predominantly in the me- of greater than 1.5. Multipoint association analysis also sial temporal cortex, brainstem, and basal ganglia. It oc- highlighted 2 other areas on chromosome 14q (adjacent curs in focal geographic isolates, including Guam and the to D14S592, 59.2 megabases [M]) and chromosome 20 Kii peninsula of Japan. The familial clustering of the dis- (adjacent to D20S470, 17.4 M) with multipoint associa- ease has suggested that a genetic factor could be impor- tion logarithm of the odds scores of greater than 2. The tant in its etiology. areas around D20S103, D14S592, and D20S470 were further analyzed by association using additional microsat- Objective: To determine whether a genetic locus could ellite markers and by conventional linkage analysis. This be identified, linked, or associated with PDC. did not provide further evidence for the role of these areas in PDC. Design and Patients: We performed a genome-wide association study of 22 Guamanian PDC and 19 control Conclusions: This study has not identified a single subjects using 834 microsatellite markers with an ap- gene locus for PDC, confirming the impression of a geo- proximate genome-wide marker density of 4.4 centi- graphic disease isolate with a complex genetic, a genetic/ morgans. environmental etiology, or a purely environmental etiology. Results: Two-point association analysis identified 17 markers (PϽ.015). Each of these markers then under- Arch Neurol. 2004;61:1889-1897

FTER WORLD WAR II, US clarified by the identification of genetic military physicians as- mutations in affected autosomal domi- signed to Guam and Na- nant families.10 These genetic advances and tional Institutes of Health the continuing familial occurrence of PDC (NIH) scientists recog- on Guam led to the consideration of a ge- nizedA that familial amyotrophic lateral scle- netic approach to this disease.11 A num- rosis (ALS) and atypical parkinsonism with ber of observations suggest that PDC may dementia (parkinsonism-dementia com- have a genetic etiology. The disease clus- plex [PDC]) were common among Cha- ters in some Guamanian Chamorro fami- morro living on Guam.1-4 These diseases lies but spares others.12-14 The disease has had been present on Guam for more than different prevalences in different vil- a century and were known as lytico, for pa- lages.15,16 The adjacent villages of Umatac ralysis, and bodig, for parkinsonism. It was and Merizo in southern Guam have simi- hoped that finding the cause of these dis- lar environments and their residents have eases would help to explain the causes of identical lifestyles, yet from 1956 to 1965, neurodegenerative diseases in the rest of the prevalence of PDC in Umatac was 274 the world. During the past 50 years, cy- per 100000 population and only 42 per cad neurotoxicity, infectious agents, and 100000 population in Merizo.15,17,18 Tra- calcium deficiency have been investi- ditionally, the populations of these vil- gated as possible causes for PDC but not lages did not intermarry. The disease may been proved to be relevant.5-9 occur in Chamorro migrants many years In recent years, the etiology of familial after they have left Guam.19-21 The dis- Author Affiliations are listed at Alzheimer disease, Parkinson disease, and ease often occurs in successive genera- the end of this article. frontotemporal dementia (FTD) has been tions and affects first-degree relatives. One

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Chamorro family in Umatac, southern Guam, is re- an immigrant population that now numbers 80000.30 Con- corded to have experienced the disease in every genera- temporary Chamorros are descended from a genetic tion since the late 1700s.2 Furthermore, a recent 40- “bottleneck” occurring 300 years (approximately 13 gen- year follow-up of a National Institutes of Health case- erations) ago, although a substantial part of the subse- control cohort shows that having an affected first- quent population growth relates to immigration. Ge- degree relative remains a risk factor for development of netic analysis of this disease assumes that a common PDC.22 Parkinsonism-dementia complex occurs in Gua- founder introduced a pathogenic mutation at an ances- manian Chamorros, but it does not seem to have af- trally distant point. The founder’s affected descendants fected the other ethnic groups who have immigrated to would share the pathogenic mutation and an adjacent Guam since World War II.23 Thus, among the many hun- chromosomal region. Genotyping of cases and control dreds of pathologically verified cases of this disease in subjects to determine shared alleles among cases should Chamorros during the past 50 years, there is only 1 clini- identify the area in which the pathogenic mutation lies. copathologic report of possible PDC in a Filipino mi- The strength of the association depends on the back- grant.24 In recent decades, the prevalence of PDC has ground frequency of the disease-associated allele in the steadily declined and the age at onset has increased.25-27 control population and decays with increasing distance This may support an exposure to a causal environmen- from the disease mutation, owing to meiotic recombi- tal factor with a cohort effect. Alternatively, this may re- nation. The background allele frequencies are un- flect increased social mobility and marrying out, thereby known a priori and may depend on whether the muta- allowing a decline in the co-occurrence of recessive ge- tion has arisen on an indigenous chromosome or has been netic factors, and/or a decrease in concurrence between introduced by an immigrant to the population. a genetic predisposition and environmental cofactors. A The evidence suggesting a genetic cause for PDC and previous report from our group has excluded the most the population structure of the affected Guamanian Cham- likely candidate gene for PDC, tau, by means of direct orro population led us to further investigate a genetic cause sequencing and microsatellite marker association.28 In the for PDC using an association analysis method. The over- present study, we have used linkage disequilibrium to lap between PDC and ALS is debated, but ALS has de- search for a PDC locus. clined in prevalence on Guam much more rapidly than Population-based disequilibrium studies involve map- PDC, such that there is only a handful of cases on the ping a disease locus by association at adjacent polymor- island at present, and ALS does not have a significantly phic genetic markers. They depend on a single gene mu- greater prevalence of disease on Guam than elsewhere. tation arising on a founder chromosome, accounting for Because of this, we decided to study PDC in isolation. a given disease in the population under study. This ap- We identified 22 apparently unrelated PDC cases and 19 proach has been used successfully in genetically iso- unrelated, neurologically asymptomatic controls for the lated populations, because they are more likely to have case-control study and selected 5 families for confirma- a single disease/single gene and mutation relationship (ge- tory linkage studies. Cases, controls, and family mem- netic and allelic homogeneity).29 They are also more likely bers underwent evaluation and selection by clinical neu- to have a sufficiently large shared chromosomal seg- rologists (J.C.S., H.R.M., K.G-H., and A.J.L.), and autopsy ment around any given marker and around a single dis- confirmation of PDC was subsequently obtained in 3 cases. ease gene mutation, depending on the age of the population and time of introduction of the mutation. An METHODS isolated population is defined as a population that is derived from a limited number of founder members and has expanded through growth rather than immigration. The CASE ASCERTAINMENT Chamorro population of Guam originated from a small number of immigrants from the Indo-Malay peninsula. All 22 cases were Chamorros with neurodegenerative symp- By the time of Magellan’s arrival in Guam in 1521, the toms beginning at ages that ranged from 54 to 74 years (de- population was 100000. However, with Spanish coloni- tailed demographic and clinical material on the 22 cases is avail- zation in the late 17th century, the native population was able from the authors on request). Eleven presented with dementia, and of these parkinsonism subsequently developed severely reduced to just 1608 by the early 1700s. The sur- in 10. Ten presented with parkinsonism, and of these demen- vivors, mostly women and children, were relocated to tia subsequently developed in 6. In the remaining case, demen- Catholic parishes on Guam, the largest and southern- tia (with paranoia) and parkinsonism occurred simulta- most island in the Mariana archipelago. Subsequently, neously. The parkinsonism usually had atypical features for the remaining Chamorro population mixed with Fili- Parkinson disease (ie, unresponsive to levodopa and involv- pino, Mexican, and Spanish immigrants who acted as ad- ing rigidity without rest tremor). In 10 of the 22 cases, fea- ministrators for the government of Guam and European tures of supranuclear gaze palsy, pseudobulbar palsy, and promi- sailors who visited the island during Pacific explora- nent axial rigidity were also seen. In the late stages of PDC, most tions.30 This new population numbered 10000 when cases had profound dementia and severe, disabling parkinson- Guam was ceded to the United States by Spain in 1899, ism. Only 2 of the 22 patients had features suggesting motor neuron disease such as amyotrophy and limb spasticity. Eleven and 30000 at the time of World War II and Japanese oc- cases were from Umatac, a village at the epicenter of the dis- cupation of the island in 1941. Since World War II, the ease, and 11 were residents of other Guam villages largely in Chamorro population has rapidly increased to 120000, the south of the island (which is 29 miles long and 4-10 miles and a large and continuing migration of Filipino, white, wide). All had a family history of PDC or ALS, and in 20 cases Asian, and other ethnic groups to Guam has resulted in a first-degree family member was affected. Thirteen of the 22

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 had pathological confirmation of PDC in themselves (n=3) or affected by neurodegenerative disease (ALS and/or PDC). Gen- in a family member (n=10). Fifteen cases died during the time eration II contained 8 members born during the time from 1865 from recruitment into the study to July 31, 1999. Genealogi- to 1884. One may have had PDC and 2 may have had ALS, as cal research after patient recruitment indicated that most of the indicated by death certificate diagnoses of “senility,” “muscle 22 PDC case-control subjects were more closely related and wasting,” and “paralysis,” respectively. Subsequent genera- could be formed into 3 kindreds (ie, 6 cases had a common tions deriving from individuals II:1 and II:8 have been docu- great-grandfather; 2 cases, a grandparent; 3 cases, a great- mented as completely as possible. Other affected members have grandparent; and 2 cases, a grandfather). Nineteen control sub- derived from II:3, II:5, and II:6. Generation III contained 30 jects were selected (age range, 65-88 years; 13 women) and, individuals, born during the years from 1879 to 1926. Five had after clinical assessment by one of us (J.C.S.), were estab- ALS and 5 had PDC. Generation IV contained 114 individu- lished to have no motor or cognitive features suggestive of PDC. als, born during the years from 1912 to 1955. Two had ALS They were the spouses of patients with PDC or healthy unre- and 22 had PDC. Autopsies in 5 of the 37 neurologically af- lated controls. Their average age at the time of sample was 76 fected members of this family confirmed the findings of PDC. years, compared with a recently estimated average age of on- Simulation of family linkage was performed using SIMLINK ver- set for PDC of 68 years.25 sion 4.12 (available at: http://hpcio.cit.nih.gov/lserver/SIMLINK .html32 (data available from the authors by request). Linkage GENOTYPING was performed using affected-only analysis under an autosomal dominant model with full penetrance and a disease allele Peripheral blood leukocytes from cases and controls were im- frequency of 0.0005. Two-point linkage was performed using mortalized to provide a robust DNA source. Using purified DNA MLINK (version 5.1; available at: http://linkage.rockefeller.edu /soft/linkage/sec3.3.html) and FASTLINK (version 4.1P; avail- extracted from these cell lines, 834 fluorescent microsatellite 33 markers were genotyped from the standard Perkin-Elmer ver- able at: http://linkage.rockefeller.edu/soft/fastlink/). Because sions 1 and 2 linkage mapping sets (Applied Biosystems, Fos- of the sizes of the pedigrees analyzed, multipoint linkage analy- ter City, Calif) and from the Research Genetics (Huntsville, Ala) sis was performed using the Monte Carlo analysis package SIM- MapPairs version 8 set. Perkin-Elmer, Inc (Wellesley, Mass) WALK2 (version 2.82; available at: http://hpcio.cit.nih.gov and Research Genetics microsatellite markers were amplified /lserver/SIMWALK2.html), after preparation with the MEGA2 package (version 2.3 available at: http://watson.hgen.pitt.edu according to the manufacturers’ instructions and analyzed us- 34,35 ing the ABI 377 DNA sequencer. We analyzed one third (276/ /mega2.html). Parametric linkage analysis was performed 834) of the markers using a DNA pooling technique in the first- using an autosomal dominant model, and the location score pass genome-wide screen. To ensure that pooling was giving in log10 units is presented, which is directly comparable to the reliable results, we retested several markers in pooled and in- LOD score. dividual samples. In addition, we reanalyzed potentially associated pooled markers using individual genotypes before fur- RESULTS ther analysis in the familial section of the study. Individual analysis always confirmed the analysis of the pooled samples. None of the markers adjacent to known loci for neuro- ALLELIC ASSOCIATION STUDY degenerative disease showed any evidence of association with PDC, with the exception of D3S2406 adjacent 36 Eight hundred thirty-four microsatellite markers were analyzed to the FTD3 locus (Table 1). Seventeen markers of the and compared in the case-control study. The average marker spac- 834 studied reached the level of significance we deter- ing was 4.4 centimorgans (cM). The allele frequencies in cases mined as the threshold for further study (PϽ.015) in a and controls were compared in a first-pass genome-wide search 2-point analysis using diseq (Table 2). Each of the 17 using a 2-point (diseq) and multipoint (dismult) association analy- markers identified in the first-pass 2-point association sis package.31 This analysis package uses a likelihood method and study was then genotyped in a conventional 2-point link- facilitates the use of multiallelic microsatellite markers in asso- age analysis study in the 5 families and analyzed using ciation studies, avoiding the loss of power that occurs in con- MLINK. None generated a LOD score greater than 3, al- ventional ␹2 testing with sparsely populated tables (ie, a large number of degrees of freedom with some very infrequently oc- though marker D20S103 generated a maximum LOD score curring genotypes). Overall, the genome-wide significance level of 1.82, close to the maximum predicted by simulation for a positive association is set at PϽ.0001 (equivalent to a loga- (Table 3). Reanalysis of the first-pass association geno- rithm of the odds [LOD] score of Ͼ3), and for a positively as- type data using a multipointlike approach with dismult sociated marker, ␭ indicates the strength of the association. Within revealed 2 areas of interest with a multipoint associa- the disequilibrium analysis, the disease allele frequency was set tion LOD score greater than 2 (Figure 2 and Figure 3). at 0.001, and for the multipoint association analysis, the inter- One area had already been detected on the 2-point (diseq) marker distances were taken form the Marshfield Medical Ge- analysis on chromosome 14q adjacent to marker D14S592 netics Web site (available at: http://www.marshfieldclinic.org (59.2 megabases [M]), and a new area on chromosome /research/genetics/Map_Markers/maps/IndexMapFrames.html; all 20 close to marker D20S470 (17.36 M) was also identi- Web sites listed in “Methods” accessed October 1, 2004). fied. These areas were reexamined with an increased marker density for 2-point and multipoint allelic asso- FAMILY ASCERTAINMENT ciation, and in a conventional family-based linkage analysis (Table 4). In addition to these areas, the telomeric Five separate Chamorro families with PDC were identified, and DNA was collected from 19 individuals. Some of these indi- chromosome 20 marker D20S103 (0.5 M) was included viduals overlap with those used in the association study as a third area of interest because of the LOD score ob- (Figure 1). The largest family was from Umatac. This family tained in the 2-point linkage analysis. Addition of fur- was traced back 4 generations to a single ancestor, born around ther markers for association and linkage around D14S592, 1840. We have traced 153 direct descendants, 37 of whom were D20S470, and D20S103 did not provide further evi-

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5 3 4 46 18 20 42 19 33 17 21

7 6 54 9 47 48 44 43 35 34 22 23

+ + + + +

8 13 56 57 58 14 11 15 16 12 10 55 50 51 49 53 52 45 36 37 38 39 40 41 24 59 26 60 25 27 28 29 30 31 32

Family 2 23

5 1 4 8

10 6 18 7 28 9

+ + + +

11 12 13 14 15 16 17 19 20 21 22 23 24 25 26 27 29 30 31 32 33 34

Family 3 12

4 3 5 6

? ? ? 10 11 14 15 16 17 19 20 21 22 18 7 8 9

12 13

Family 4 Family 5 2 1 12

+ +

4 3 10 9 3 4 6 7 8 5

+ + +

7 19 5 6 8 12 13 14 15 16 11 17 18

Figure 1. Five families used for genetic linkage studies. ALS indicates amyotrophic lateral sclerosis; PDC, parkinsonism-dementia complex; circles, females; question mark, diagnosis uncertain; slashes, deceased; squares, males; and diamonds, male or female subjects, disguised to preserve confidentiality.

dence of a role for these areas in the pathogenesis of PDC earliest investigators to be primarily genetic in etiol- (Table 4), and the multipoint linkage in families ex- ogy.28,37-39 Parkinsonism-dementia complex shows no evi- cluded these areas. dence of association with markers corresponding to known neurodegenerative disease loci, with the excep- COMMENT tion of the marker adjacent to FT33. However, the FTD3 locus was not linked to PDC in the family study, and Although there have been a number of candidate gene pathological differences between PDC and FTD-3 sug- studies of PDC and ALS on Guam, this study is, to our gest that these are unlikely to be allelic disorders.36 Con- knowledge, the first genome-wide screen for neurode- firming the earlier study from our group, we have not generative disease on Guam, which was thought by the found evidence for an association between PDC and tau.

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Recently, another group has reported an association be- A number of factors may limit the present study. tween a microsatellite marker within the tau region and Although the extent and mode of inheritance of the PDC.40 However, they confirm that most markers in the genetic influence on PDC is unknown, a recent tau region, including tau intragenic markers, are not as- follow-up case-control analysis of PDC confirms the sociated with PDC. Furthermore, no associated or linked previously reported excess risk in first-degree relatives haplotype is related to PDC, and thus, these findings are of patients with PDC compared with their spouses.22 of uncertain significance. Our study has provided evi- The relationship between PDC and ALS remains dence of areas of possible association between PDC and unclear. This study confirms the previous findings that areas on chromosomes 20p, 20ptel, and 14. However these some patients with PDC may have a family history of associations do not reach a level consistent with genome- ALS, suggesting that there may be some common wide significance. In addition, a family-based replica- genetic or environmental factor/cause. There are also tion study looking at the areas identified has not con- grounds for believing that PDC and ALS may be sepa- firmed the results obtained in the case-control analysis. rate diseases, because the prevalence of ALS has declined much more rapidly than that of PDC. The decline in the prevalence of both PDC and ALS and the Table 1. Two-Point Association Study and Familial Linkage co-occurrence of an ocular and probably infective dis- Analysis for Markers With LRT PϽ.015* ease (Guam retinal pigmentary epitheliopathy) are compatible with the notion that an environmental fac- 2-Point Linkage tor may be important in the etiology of PDC.41-43 A Association Analysis Analysis genetic risk factor may be widely distributed in the Locus LRT ␭ P Value ␪ LOD population of Guam, and in these circumstances an D14S592 11.41 0.50 .0004 0.2 0.40 association study may not detect a genetic locus. Also, ATA59H06 (chr9) 8.51 0.25 .0018 0.35 0.08 our sample may have been underpowered in both the D2S326 8.20 0.44 .002 0.2 0.39 association and the family analyses. In fact, the power D18S976 7.13 0.33 .004 0.25 0.10 to detect an association between an allele of a microsat- D3S2406 6.44 0.25 .006 0.1 0.78 ellite marker and PDC is about 59% in the best-case D1S468 6.38 0.32 .006 0.2 0.25 scenario (␣=.015; frequency of the associated allele, D16S2624 6.16 0.49 .006 0.35 0.08 D12S375 6.15 0.52 .007 0.4 −0.030 0.05; assuming a relative risk conferred by the risk D3S1271 6.10 0.45 .007 0.05 0.11 allele of 5.0, frequency of the disease of 0.15, and the D20S103 5.92 0.52 .008 0.0 1.82 extent of linkage disequilibrium between the marker D2S319 5.65 0.44 .009 0.4 −0.02 and the disease [DЈ] of 0.9). The family population col- D11S925 4.90 0.31 .010 0.4 0.03 lected may also be underpowered. The simulations per- D5S2505 5.28 0.42 .01 0.1 1.01 formed show that the LOD score that could be obtained D2S160 5.10 0.34 .01 0.4 −0.04 D4S403 5.06 0.60 .01 0.4 −0.03 for a linked marker would be around 1.5 for the marker D4S412 4.87 0.41 .01 0.15 0.34 density used in this study (Table 3). The use of a com- D13S171 4.82 0.47 .01 0.4 0.050 bined association followed by a linkage study is the D11S908 4.74 0.31 .02 0.1 0.22 most rigorous approach to defining a genetic area of interest. However, this approach will not only tend to Abbreviations: chr9, chromosome 9; likelihood ratio; LOD, logarithm of minimize the chance of identifying a false-positive odds; LRT, likelihood ratio test (␹2 value); ␪, recombination fraction. *No marker identified in the association study as being possibly result but also reduce the overall power of the study. associated reached a LOD score level (Ͼ3) consistent with linkage. Therefore, despite the negative linkage results, the areas

Table 2. Two-Point Association Analyses (dislamb) of PDC and Existing Loci for Neurodegenerative Disease

Disease STS Map Marshfield Map Marker Marshfield Map Locus Gene Ch Position on Ch Position Locus, cM Analyzed Position Locus, cM LRT P Value ␭ PARK-1 SNCA 487M99 D4S414 101 0.0 .50 0.0 PARK-2 Parkin 6 170 M 179 D6S624 179 0.0 .50 0.0 PARK-3 267M88 D2S285 86 0.0 .50 0.0 PARK-4 429M41 D4S2397 43 0.0 .50 0.0 PARK-5 UCHL1 442M50 D4S2632 52 0.0 .50 0.0 PARK-6 1 15.5 M 49 D1S552 45 0.0 .50 0.0 PARK-7 1 5.4 M 14 D1S214 14 3.7 .03 0.4 APP APP 21 24 M 21 D21S1253 20 0.0 .50 0.0 PS-1 PS1 14 67 M 85 D14S53 86 0.0 .50 0.0 PS-2 PS2 1 234 M 245 D1S2800 252 0.0 .50 0.0 FTD-3 3 74 M 103 D3S2406 102 6.4 .006 0.3 FTD-9 9 71.4 M 80 D9S922 80 0.0 .50 0.0 FTDP-17 TAU 17 45.5 M 65 D17S791 64 0.0 .50 0.0

Abbreviations: APP, amyloid precursor protein; Ch, chromosome; cM, centimorgans; FTD, frontotemporal dementia; ␭, relative risk to siblings; LRT, likelihood ratio test (␹2 value); M, megabases; PARK, Parkinson disease locus; PS, presenilin; STS, sequence-tagged site; UCHL1, gene for ubiquitin C terminal hydrolase 1.

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 defined in the association study may still be relevant to wide association studies is difficult to predict, because the etiology of PDC. In this study, the LOD obtained it depends on unknown factors such as the number of with marker D20S103 was 1.82. Simulation analysis generations since the mutation arose or was introduced suggests that the probability of an unlinked marker into the population and the background frequency of as- reaching a LOD of this level would be less than 0.1%. sociated alleles in the normal population. Because of the Despite the lack of linkage or association with makers severe reduction of the Chamorro population by 1720, adjacent to D20S103, this may still emerge as an impor- we assume that the mutation has propagated in the popu- tant area in the pathogenesis of PDC. lation for approximately 13 generations. Under a free- Another limitation of this study may arise from the mating scheme, the average genetic separation between marker density used and the size of the shared chromo- the most distant relations who share a single ancestor from somal segment in PDC cases. The power of genome- 1730 is approximately 26 meioses. This indicates an average shared chromosomal region of around 4 cM (at this distance recombination events occurring 4 times in ev- Table 3. Simulation of Family Linkage Analysis of Guam Families With PDC* ery 100 meioses), which falls within the density used in the genome screen. The genealogical studies illustrate that Summed Mean Maximum LOD Score cases studied in the genome screen are more closely re- Probability lated than 22 meioses, introducing the possibility that ␪ LOD Score Ͼ3.0 Summed 12345 false-positive regions may exist because of kinship, al- 0.00 0.0 1.9 1.2 0.21 0.29 0.23 0.13 though it is unlikely that this would prevent the detec- 0.025 0.0 1.6 1.0 0.23 0.29 0.22 0.11 tion of truly associated areas. 0.050 0.0 1.2 0.83 0.19 0.25 0.22 0.10 Identifying the cause of this disorder is complicated 0.50 0.0 0.1 0.08 0.10 0.15 0.1 0.08 by the virtual disappearance of ALS from Guam and the delayed onset and decline of the PDC syndrome. An Abbreviations: LOD, logarithm of odds; ␪, recombination fraction. *Indicates disease penetrance of 0.4 by 75 years of age in autosomal ill-defined entity termed Marianas dementia occurs dominant linked marker LOD score analysis. on Guam, but unlike PDC and ALS, this entity is not

3.0 Chromosome 1 Chromosome 2 Chromosome 3 1.0 0.8 2.0 0.6 γ

LOD 0.4 1.0 0.2 0.0 0.0

3.0 Chromosome 4 Chromosome 5 Chromosome 6 1.0 0.8 2.0 0.6 γ

LOD 0.4 1.0 0.2 0.0 0.0

3.0 Chromosome 7 Chromosome 8 Chromosome 9 1.0 0.8 2.0 0.6 γ

LOD 0.4 1.0 0.2 0.0 0.0

3.0 Chromosome 10 Chromosome 11 Chromosome 12 1.0 0.8 2.0 0.6 γ

LOD 0.4 1.0 0.2 0.0 0.0

0.0 0.5 1.0 1.5 2.0 2.5 3.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Distance, cM × 10–2 Distance, cM × 10–2 Distance, cM × 10–2

Figure 2. First-pass genome-wide multipoint association study of parkinsonism-dementia complex for chromosomes 1 through 12. cM indicates centimorgans; ␭, likelihood ratio; LOD, logarithm of odds; triangles, ␭ association; and straight line, LOD score.

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LOD 0.4 1.0 0.2 0.0 0.0

3.0 Chromosome 16 Chromosome 17 Chromosome 18 1.0 0.8 2.0 0.6 γ

LOD 0.4 1.0 0.2 0.0 0.0

3.0 Chromosome 19 Chromosome 20 Chromosome 21 1.0 0.8 2.0 0.6 γ

LOD 0.4 1.0 0.2 0.0 0.0

0.0 0.5 1.0 1.5 2.0 2.5 3.0 Distance, cM × 10–2

3.0 Chromosome 22 Chromosome X 1.0 0.8 2.0 0.6 γ

LOD 0.4 1.0 0.2 0.0 0.0

0.0 0.5 1.0 1.5 2.0 2.5 3.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Distance, cM × 10–2 Distance, cM × 10–2

Figure 3. First-pass genome-wide multipoint association study of parkinsonism-dementia complex for chromosomes 13 through 22 and X. cM indicates centimorgans; ␭, likelihood ratio; and LOD, logarithm of odds.

Table 4. Detailed Analysis of Areas of Interest Identified in the Study

2-Point Association 2-Point Linkage Multipoint Linkage SIMWALK2* Multipoint 2 Markers Mb Maximum LOD Score Location Score, log10 U LRT, ␹ P Value ␭ Association, LOD D14S274 55.4 ND ND 0 .50 0 0 D14S601 57.2 −0.074 −13.75 0 .50 0 0 D14S1038 57.3 1 −13.70 ND ND ND ND D14S994 58.5 −0.085 −13.80 0 .50 0 0 D14S592 59.2 0.4 −13.92 11.4 .0004 0.4966 2.48 D14S1059 61.3 −0.001 −13.95 1.25 .13 0.252 0.27 D14S1012 61.6 −0.056 −14.4 0 .50 0 0 D20S1155 0.071 −0.018 −13.91 0 .50 0 0 D20S103 0.547 1.82 −13.91 5.9 .008 0.52 0.005 D20S117 0.643 −0.11 −13.98 0 .50 0 0.006 D20S113 2.023 −0.021 −13.53 3.3 .04 0.44 0.002 D20S193 3.301 −0.12 −11.27 0 .50 0 0.003 D20S875 16.64 0.66 −4.28 0 .50 0 0 D20S48 17.3 0.12 −8.48 0 .50 0 0.007 D20s470 17.36 0.48 −8.91 4.6 .02 0.32 0.395 D20s475 18.11 −0.02 −7.21 0 .50 0 0 D20s40 19.22 0.64 −6.60 0 .50 0 0

Abbreviations: ␭, relative risk to siblings; LOD, logarithm of odds; LRT, likelihood ratio test (␹2 value); Mb, megabases; ND, analysis not done. *Multipoint linkage analysis performed using the Monte Carlo analysis package. SIMWALK2 version 2.82 analysis software is available at: http://hpcio.cit.nih .gov/lserver/SIMWALK2.html (accessed October 1, 2004).

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 particularly common in the south of the island in Uma- Farrer and Perez-Tur. Obtained funding: Wood, Lees, tac, and so its relationship to ALS and to PDC is even Siddique, and Hardy. Administrative, technical, and ma- more obscure than their relation to each other. The terial support: Steele, Crook, Warvrant-De Vrièze, and number of remaining cases of PDC on Guam is esti- Siddique. Study supervision: Wood, Lees, Hardy, and mated to be around 100. Although this study could be Perez-Tur. extended to a larger living affected population at this Funding/Support: This study was supported in part by stage, it is likely to be more rewarding to define the funding from the National Institutes of Health, Bethesda, relationship of Marianas dementia to PDC. If this dis- Md; The Progressive Supranuclear Palsy (Europe) Asso- ease’s pathologic characteristic is a neurofibrillary ciation, Northants, England; and the Medical Research tangle only, similar to that seen in PDC, then this Council UK, London, England. observation would identify a much larger pool of affected subjects for genetic studies. The shifts in prevalence provide compelling evidence of an environmental REFERENCES role, but they do not explain the strong familial rela- 1. Zimmerman H. Progress Report of Work in the Laboratory of Pathology During tionships. We failed to find evidence of a single genetic May, 1945. Guam. Washington, DC: US Naval Medical Research Unit; 1945. locus, which seems very unlikely given the data pre- 2. Mulder DW, Kurland LT, Iriarte LLG. Neurologic diseases on the island of Guam. sented in the current study. It does not rule out more US Armed Forces Med J. 1954;5:1724-1739. complex genetic or genetic-environmental causes. How- 3. 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