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• W2023922415 abstract "Alzheimer disease (AD) is the most common cause of dementia. We conducted a genome screen of 103 patients with late-onset AD who were ascertained as part of the Genetic Research in Isolated Populations (GRIP) program that is conducted in a recently isolated population from the southwestern area of The Netherlands. All patients and their 170 closely related relatives were genotyped using 402 microsatellite markers. Extensive genealogy information was collected, which resulted in an extremely large and complex pedigree of 4,645 members. The pedigree was split into 35 subpedigrees, to reduce the computational burden of linkage analysis. Simulations aiming to evaluate the effect of pedigree splitting on false-positive probabilities showed that a LOD score of 3.64 corresponds to 5% genomewide type I error. Multipoint analysis revealed four significant and one suggestive linkage peaks. The strongest evidence of linkage was found for chromosome 1q21 (heterogeneity LOD [HLOD]=5.20 at marker D1S498). Approximately 30 cM upstream of this locus, we found another peak at 1q25 (HLOD=4.0 at marker D1S218). These two loci are in a previously established linkage region. We also confirmed the AD locus at 10q22-24 (HLOD=4.15 at marker D10S185). There was significant evidence of linkage of AD to chromosome 3q22-24 (HLOD=4.44 at marker D3S1569). For chromosome 11q24-25, there was suggestive evidence of linkage (HLOD=3.29 at marker D11S1320). We next tested for association between cognitive function and 4,173 single-nucleotide polymorphisms in the linked regions in an independent sample consisting of 197 individuals from the GRIP region. After adjusting for multiple testing, we were able to detect significant associations for cognitive function in four of five AD-linked regions, including the new region on chromosome 3q22-24 and regions 1q25, 10q22-24, and 11q25. With use of cognitive function as an endophenotype of AD, our study indicates the that the RGSL2, RALGPS2, and C1orf49 genes are the potential disease-causing genes at 1q25. Our analysis of chromosome 10q22-24 points to the HTR7, MPHOSPH1, and CYP2C cluster. This is the first genomewide screen that showed significant linkage to chromosome 3q23 markers. For this region, our analysis identified the NMNAT3 and CLSTN2 genes. Our findings confirm linkage to chromosome 11q25. We were unable to confirm SORL1; instead, our analysis points to the OPCML and HNT genes. Alzheimer disease (AD) is the most common cause of dementia. We conducted a genome screen of 103 patients with late-onset AD who were ascertained as part of the Genetic Research in Isolated Populations (GRIP) program that is conducted in a recently isolated population from the southwestern area of The Netherlands. All patients and their 170 closely related relatives were genotyped using 402 microsatellite markers. Extensive genealogy information was collected, which resulted in an extremely large and complex pedigree of 4,645 members. The pedigree was split into 35 subpedigrees, to reduce the computational burden of linkage analysis. Simulations aiming to evaluate the effect of pedigree splitting on false-positive probabilities showed that a LOD score of 3.64 corresponds to 5% genomewide type I error. Multipoint analysis revealed four significant and one suggestive linkage peaks. The strongest evidence of linkage was found for chromosome 1q21 (heterogeneity LOD [HLOD]=5.20 at marker D1S498). Approximately 30 cM upstream of this locus, we found another peak at 1q25 (HLOD=4.0 at marker D1S218). These two loci are in a previously established linkage region. We also confirmed the AD locus at 10q22-24 (HLOD=4.15 at marker D10S185). There was significant evidence of linkage of AD to chromosome 3q22-24 (HLOD=4.44 at marker D3S1569). For chromosome 11q24-25, there was suggestive evidence of linkage (HLOD=3.29 at marker D11S1320). We next tested for association between cognitive function and 4,173 single-nucleotide polymorphisms in the linked regions in an independent sample consisting of 197 individuals from the GRIP region. After adjusting for multiple testing, we were able to detect significant associations for cognitive function in four of five AD-linked regions, including the new region on chromosome 3q22-24 and regions 1q25, 10q22-24, and 11q25. With use of cognitive function as an endophenotype of AD, our study indicates the that the RGSL2, RALGPS2, and C1orf49 genes are the potential disease-causing genes at 1q25. Our analysis of chromosome 10q22-24 points to the HTR7, MPHOSPH1, and CYP2C cluster. This is the first genomewide screen that showed significant linkage to chromosome 3q23 markers. For this region, our analysis identified the NMNAT3 and CLSTN2 genes. Our findings confirm linkage to chromosome 11q25. We were unable to confirm SORL1; instead, our analysis points to the OPCML and HNT genes. Alzheimer disease (AD) is a progressive neurodegenerative disorder that accounts for the vast majority of dementia. The population prevalence of the disease rises steeply with age from <2% at age 65 years to >35% after age 90 years.1Ott A Breteler MM van Harskamp F Claus JJ van der Cammen TJ Grobbee DE Hofman A Prevalence of Alzheimer’s disease and vascular dementia: association with education.BMJ. 1995; 310: 970-973Crossref PubMed Scopus (672) Google Scholar, 2Rocca WA Hofman A Brayne C Breteler MM Clarke M Copeland JR Dartigues JF Engedal K Hagnell O Heeren TJ et al.Frequency and distribution of Alzheimer’s disease in Europe: a collaborative study of 1980-1990 prevalence findings.Ann Neurol. 1991; 30: 381-390Crossref PubMed Scopus (345) Google Scholar Family history is an important indicator of risk of AD, and, in a large number of families, the disease segregates as an autosomal dominant trait. The heritability for AD was recently estimated to be 79%.3Gatz M Reynolds CA Fratiglioni L Johansson B Mortimer JA Berg S Fiske A Pedersen NL Role of genes and environments for explaining Alzheimer disease.Arch Gen Psychiatry. 2006; 63: 168-174Crossref PubMed Scopus (888) Google Scholar Several dominant mutations have been identified, including mutations in the presenilin 1 (PSEN1 [MIM 104311]),4Sherrington R Rogaev EI Liang Y Rogaeva EA Levesque G Ikeda M Chi H Lin C Li G Holman K et al.Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease.Nature. 1995; 375: 754-760Crossref PubMed Scopus (3420) Google Scholar presenilin 2 (PSEN2 [MIM 600759]),5Levy-Lahad E Wasco W Poorkaj P Romano DM Oshima J Pettingell WH Yu CE Jondro PD Schmidt SD Wang K et al.Candidate gene for the chromosome 1 familial Alzheimer’s disease locus.Science. 1995; 269: 973-977Crossref PubMed Scopus (2141) Google Scholar, 6Rogaev EI Sherrington R Rogaeva EA Levesque G Ikeda M Liang Y Chi H Lin C Holman K Tsuda T et al.Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene.Nature. 1995; 376: 775-778Crossref PubMed Scopus (1712) Google Scholar and amyloid precursor protein (APP [MIM 104760]) genes.7Goate A Chartier-Harlin MC Mullan M Brown J Crawford F Fidani L Giuffra L Haynes A Irving N James L et al.Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease.Nature. 1991; 349: 704-706Crossref PubMed Scopus (3589) Google Scholar A common polymorphism (ɛ4) in the gene encoding apolipoprotein E (APOE [MIM 107741]) increases susceptibility to both early- and late-onset AD.8van Duijn CM de Knijff P Cruts M Wehnert A Havekes LM Hofman A Van Broeckhoven C Apolipoprotein E4 allele in a population-based study of early-onset Alzheimer’s disease.Nat Genet. 1994; 7: 74-78Crossref PubMed Scopus (389) Google Scholar, 9Corder EH Saunders AM Strittmatter WJ Schmechel DE Gaskell PC Small GW Roses AD Haines JL Pericak-Vance MA Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families.Science. 1993; 261: 921-923Crossref PubMed Scopus (6759) Google Scholar These four genes together explain less than a quarter of the disease prevalence, indicating that additional genetic risk factors remain to be identified.10Sleegers K Van Duijn CM Alzheimer’s disease: genes, pathogenesis and risk prediction.Community Genet. 2001; 4: 197-203Crossref PubMed Scopus (28) Google Scholar, 11Bertram L Tanzi RE The genetic epidemiology of neurodegenerative disease.J Clin Invest. 2005; 115: 1449-1457Crossref PubMed Scopus (411) Google Scholar In addition to APOE, various candidate genes were reported to be associated with late-onset AD. In most cases, findings have not been consistently replicated.12Tanzi RE Bertram L New frontiers in Alzheimer’s disease genetics.Neuron. 2001; 32: 181-184Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar, 13Myers AJ Goate AM The genetics of late-onset Alzheimer’s disease.Curr Opin Neurol. 2001; 14: 433-440Crossref PubMed Scopus (67) Google Scholar A large meta-analysis of all genes studied so far pinpointed 13 potential AD-susceptibility genes: angiotensin I converting enzyme (ACE [MIM 106180]); cholinergic receptor, nicotinic, beta 2 (CHRNB2 [MIM 118507]); cystatin C (CST3 [MIM 604312]); estrogen receptor 1 (ESR1 [MIM 133430]); glyceraldehyde-3-phosphate dehydrogenase, spermatogenic (GAPDHS [MIM 609169]); insulin-degrading enzyme (IDE [MIM 146680]); 5,10-methylenetetrahydrofolate reductase (MTHFR [MIM 607093]); nicastrin (NCSTN [MIM 605254]); prion protein (PRNP [MIM 176640]); PSEN1; transferrin (TF [MIM 190000]); transcription factor A, mitochondrial (TFAM [MIM 600438]); and tumor necrosis factor (TNF [MIM 191160]).14Bertram L McQueen MB Mullin K Blacker D Tanzi RE Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database.Nat Genet. 2007; 39: 17-23Crossref PubMed Scopus (1353) Google Scholar Furthermore, genome screens targeting AD loci have been conducted. As reviewed online by the Alzheimer Research Forum, the replicated regions from previous genome screens include 1p36, 1q21-31, 2p23-24, 4q35, 5p13-15, 6p21, 6q15-16, 6q25-27, 9p21-22, 10q21-22, 10q25, 12p11-12, 19q13, 21q21-22, and Xp11-21.9Corder EH Saunders AM Strittmatter WJ Schmechel DE Gaskell PC Small GW Roses AD Haines JL Pericak-Vance MA Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families.Science. 1993; 261: 921-923Crossref PubMed Scopus (6759) Google Scholar, 15Kehoe P Wavrant-De Vrieze F Crook R Wu WS Holmans P Fenton I Spurlock G Norton N Williams H Williams N et al.A full genome scan for late onset Alzheimer’s disease.Hum Mol Genet. 1999; 8: 237-245Crossref PubMed Scopus (321) Google Scholar, 16Pericak-Vance MA Bass MP Yamaoka LH Gaskell PC Scott WK Terwedow HA Menold MM Conneally PM Small GW Vance JM et al.Complete genomic screen in late-onset familial Alzheimer disease: evidence for a new locus on chromosome 12.JAMA. 1997; 278: 1237-1241Crossref PubMed Google Scholar, 17Pericak-Vance MA Grubber J Bailey LR Hedges D West S Santoro L Kemmerer B Hall JL Saunders AM Roses AD et al.Identification of novel genes in late-onset Alzheimer’s disease.Exp Gerontol. 2000; 35: 1343-1352Crossref PubMed Scopus (159) Google Scholar, 18Curtis D North BV Sham PC A novel method of two-locus linkage analysis applied to a genome scan for late onset Alzheimer’s disease.Ann Hum Genet. 2001; 65: 473-481Crossref PubMed Scopus (26) Google Scholar, 19Olson JM Goddard KA Dudek DM A second locus for very-late-onset Alzheimer disease: a genome scan reveals linkage to 20p and epistasis between 20p and the amyloid precursor protein region.Am J Hum Genet. 2002; 71: 154-161Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 20Myers A Holmans P Marshall H Kwon J Meyer D Ramic D Shears S Booth J DeVrieze FW Crook R et al.Susceptibility locus for Alzheimer’s disease on chromosome 10.Science. 2000; 290: 2304-2305Crossref PubMed Scopus (340) Google Scholar, 21Li Y-J Scott WK Hedges DJ Zhang F Gaskell PC Nance MA Watts RL Hubble JP Koller WC Pahwa R et al.Age at onset in two common neurodegenerative diseases is genetically controlled.Am J Hum Genet. 2002; 70: 985-993Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar, 22Blacker D Bertram L Saunders AJ Moscarillo TJ Albert MS Wiener H Perry RT Collins JS Harrell LE Go RC et al.Results of a high-resolution genome screen of 437 Alzheimer’s disease families.Hum Mol Genet. 2003; 12: 23-32Crossref PubMed Scopus (300) Google Scholar, 23Goddard KA Olson JM Payami H van der Voet M Kuivaniemi H Tromp G Evidence of linkage and association on chromosome 20 for late-onset Alzheimer disease.Neurogenetics. 2004; 5: 121-128Crossref PubMed Scopus (21) Google Scholar, 24Holmans P Hamshere M Hollingworth P Rice F Tunstall N Jones S Moore P Wavrant DeVrieze F Myers A Crook R et al.Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer’s disease.Am J Med Genet B Neuropsychiatr Genet. 2005; 135: 24-32Crossref Scopus (59) Google Scholar, 25Zubenko GS Hughes HB Stiffler JS Hurtt MR Kaplan BB A genome survey for novel Alzheimer disease risk loci: results at 10-cM resolution.Genomics. 1998; 50: 121-128Crossref PubMed Scopus (89) Google Scholar, 26Hiltunen M Mannermaa A Thompson D Easton D Pirskanen M Helisalmi S Koivisto AM Lehtovirta M Ryynanen M Soininen H Genome-wide linkage disequilibrium mapping of late-onset Alzheimer’s disease in Finland.Neurology. 2001; 57: 1663-1668Crossref PubMed Scopus (72) Google Scholar, 27Farrer LA Bowirrat A Friedland RP Waraska K Korczyn AD Baldwin CT Identification of multiple loci for Alzheimer disease in a consanguineous Israeli-Arab community.Hum Mol Genet. 2003; 12: 415-422Crossref PubMed Scopus (116) Google Scholar, 28Wijsman EM Daw EW Yu C-E Payami H Steinbart EJ Nochlin D Conlon EM Bird TD Schellenberg GD Evidence for a novel late-onset Alzheimer disease locus on chromosome 19p13.2.Am J Hum Genet. 2004; 75: 398-409Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 29Ashley-Koch AE Shao Y Rimmler JB Gaskell PC Welsh-Bohmer KA Jackson CE Scott WK Haines JL Pericak-Vance MA An autosomal genomic screen for dementia in an extended Amish family.Neurosci Lett. 2005; 379: 199-204Crossref PubMed Scopus (26) Google Scholar Several genes have been suggested to explain the linkage to chromosome 9, 10, 12, and 19, but, so far, these genes also remain to be confirmed. Finally, there is evidence of linkage to chromosome 11,22Blacker D Bertram L Saunders AJ Moscarillo TJ Albert MS Wiener H Perry RT Collins JS Harrell LE Go RC et al.Results of a high-resolution genome screen of 437 Alzheimer’s disease families.Hum Mol Genet. 2003; 12: 23-32Crossref PubMed Scopus (300) Google Scholar which was explained recently by the identification of SORL1 (MIM 602005).30Rogaeva E Meng Y Lee JH Gu Y Kawarai T Zou F Katayama T Baldwin CT Cheng R Hasegawa H et al.The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.Nat Genet. 2007; 39: 168-177Crossref PubMed Scopus (836) Google Scholar Each of the established loci for AD (APP, PSEN1, PSEN2, and APOE) was initially localized by linkage analyses. However, pedigrees suitable for localizing genes have become scarce, particularly for late-onset forms of AD. Genetically isolated populations provide opportunities for linkage analysis. With use of genealogical records, extended pedigrees can be constructed. Furthermore, the complexity of disease may be reduced in terms of number of genes involved, particularly for rare Mendelian forms.31Varilo T Peltonen L Isolates and their potential use in complex gene mapping efforts.Curr Opin Genet Dev. 2004; 14: 316-323Crossref PubMed Scopus (91) Google Scholar, 32Pardo LM MacKay I Oostra B van Duijn CM Aulchenko YS The effect of genetic drift in a young genetically isolated population.Ann Hum Genet. 2005; 69: 288-295Crossref PubMed Scopus (110) Google Scholar Linkage analysis of complex traits has been used successfully in Iceland for complex diseases such as type 2 diabetes and stroke,33Escamilla MA Population isolates: their special value for locating genes for bipolar disorder.Bipolar Disord. 2001; 3: 299-317Crossref PubMed Scopus (37) Google Scholar, 34Helgason A Yngvadottir B Hrafnkelsson B Gulcher J Stefansson K An Icelandic example of the impact of population structure on association studies.Nat Genet. 2005; 37: 90-95PubMed Google Scholar whereas, for AD, genome screens have been conducted successfully with Caribbean Hispanics.35Lee JH Cheng R Santana V Williamson J Lantigua R Medrano M Arriaga A Stern Y Tycko B Rogaeva E et al.Expanded genomewide scan implicates a novel locus at 3q28 among Caribbean Hispanics with familial Alzheimer disease.Arch Neurol. 2006; 63: 1591-1598Crossref PubMed Scopus (30) Google Scholar We have followed this approach in a genetically isolated community from the southwestern area of The Netherlands, as part of the Genetic Research in Isolated Populations (GRIP) program.36Sleegers K Roks G Theuns J Aulchenko YS Rademakers R Cruts M van Gool WA Van Broeckhoven C Heutink P Oostra BA et al.Familial clustering and genetic risk for dementia in a genetically isolated Dutch population.Brain. 2004; 127: 1641-1649Crossref PubMed Scopus (59) Google Scholar A total of 103 patients with late-onset AD were ascertained and were included in a large pedigree on the basis of genealogical records. In this study, we present a genomewide screen of these families. The linkage analysis was followed by an association study of cognitive function in a series of 197 unrelated and nondemented people from the GRIP region who were extensively characterized by a cognitive battery. To further investigate the evidence of linkage, the regions identified in the linkage study were characterized with a dense panel of SNPs. Decline in cognitive function, particularly mild cognitive impairment, is an early predictor of AD,37Geerlings MI Jonker C Bouter LM Ader HJ Schmand B Association between memory complaints and incident Alzheimer’s disease in elderly people with normal baseline cognition.Am J Psychiatry. 1999; 156: 531-537PubMed Google Scholar, 38Tierney MC Szalai JP Snow WG Fisher RH Nores A Nadon G Dunn E St George-Hyslop PH Prediction of probable Alzheimer’s disease in memory-impaired patients: a prospective longitudinal study.Neurology. 1996; 46: 661-665Crossref PubMed Scopus (517) Google Scholar, 39Jonker C Geerlings MI Schmand B Are memory complaints predictive for dementia?. A review of clinical and population-based studies.Int J Geriatr Psychiatry. 2000; 15: 983-991Crossref PubMed Scopus (609) Google Scholar and the heritability of cognitive function is as high as 56%, which suggests that cognition is a valuable endophenotype.40Ando J Ono Y Wright MJ Genetic structure of spatial and verbal working memory.Behav Genet. 2001; 31: 615-624Crossref PubMed Scopus (165) Google Scholar, 41McClearn GE Johansson B Berg S Pedersen NL Ahern F Petrill SA Plomin R Substantial genetic influence on cognitive abilities in twins 80 or more years old.Science. 1997; 276: 1560-1563Crossref PubMed Scopus (539) Google Scholar, 42Swan GE Reed T Jack LM Miller BL Markee T Wolf PA DeCarli C Carmelli D Differential genetic influence for components of memory in aging adult twins.Arch Neurol. 1999; 56: 1127-1132Crossref PubMed Scopus (53) Google Scholar Further, memory function was found to be an endophenotype for families multiply affected with AD.43Lee JH Flaquer A Stern Y Tycko B Mayeux R Genetic influences on memory performance in familial Alzheimer disease.Neurology. 2004; 62: 414-421Crossref PubMed Scopus (29) Google Scholar This study was performed within the framework of the previously described GRIP program.43Lee JH Flaquer A Stern Y Tycko B Mayeux R Genetic influences on memory performance in familial Alzheimer disease.Neurology. 2004; 62: 414-421Crossref PubMed Scopus (29) Google Scholar, 44van Duijn CM Dekker MC Bonifati V Galjaard RJ Houwing-Duistermaat JJ Snijders PJ Testers L Breedveld GJ Horstink M Sandkuijl LA et al.Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36.Am J Hum Genet. 2001; 69: 629-634Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar, 45Aulchenko YS Heutink P Mackay I Bertoli-Avella AM Pullen J Vaessen N Rademaker TA Sandkuijl LA Cardon L Oostra B et al.Linkage disequilibrium in young genetically isolated Dutch population.Eur J Hum Genet. 2004; 12: 527-534Crossref PubMed Scopus (80) Google Scholar The Medical Ethics Committee of the Erasmus Medical Center approved study protocol. The GRIP population is a genetically isolated community in the southwestern area of The Netherlands. Fewer than 400 individuals were present in the region in the middle of the 18th century. Considerable population growth occurred in 1850–1900, as was the case in many European populations. An estimated 20,000 descendants of the population are now scattered over eight adjacent communities. There was minimal immigration. The genealogical database currently contains information about 107,091 people spanning 23 generations. Residents in the GRIP area are generally related via multiple lines of descent and are inbred via multiple consanguineous loops.45Aulchenko YS Heutink P Mackay I Bertoli-Avella AM Pullen J Vaessen N Rademaker TA Sandkuijl LA Cardon L Oostra B et al.Linkage disequilibrium in young genetically isolated Dutch population.Eur J Hum Genet. 2004; 12: 527-534Crossref PubMed Scopus (80) Google Scholar Patients with AD were traced through general practitioners, neurologists, and nursing-home physicians. Data relevant for the diagnosis of AD were collected by a research physician, and the diagnosis of AD was verified by two independent neurologists with criteria of the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association.46McKhann G Drachman D Folstein M Katzman R Price D Stadlan EM Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease.Neurology. 1984; 34: 939-944Crossref PubMed Google Scholar Data about the presence of AD, parkinsonism, essential tremor, and dementia were collected for first-, second-, and third-degree relatives by means of a family-history questionnaire. First-degree relatives also underwent a brief neurological examination. All patients and their relatives who were invited to participate in our study provided informed consent. A total of 112 probable patients with late-onset AD (age at onset ⩾65 years, mean age [±SD] at onset 75±5.3 years) and 170 unaffected first-degree relatives (mean age 63.5±13.1 years; range 40–102 years) were ascertained. Tracing the genealogy of the 112 probable patients with late-onset AD, we were able to include 103 patients in a single pedigree containing 4,645 individuals in 18 generations, as depicted in figure 1. The other nine patients were singletons and therefore were not included in the linkage analysis. This large pedigree showed multiple, distant lines of descent and consanguineous loops (table 1). The average kinship coefficient among patients was 0.0018. This value is between a third cousin once removed and a fourth cousin. Using such a pedigree in linkage analysis is computationally impossible. A common approach to reduce the computational complexity is to split the large pedigree into smaller and computable units. For this purpose, we used a kinship clustering method that is similar to the maximal-cliques-partitioning method proposed by Falchi et al,47Falchi M Forabosco P Mocci E Borlino CC Picciau A Virdis E Persico I Parracciani D Angius A Pirastu M A genomewide search using an original pairwise sampling approach for large genealogies identifies a new locus for total and low-density lipoprotein cholesterol in two genetically differentiated isolates of Sardinia.Am J Hum Genet. 2004; 75: 1015-1031Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar and we added a restriction that the resulting subpedigrees have no more than 35 bits, where the bit size is twice the number of founders minus the number of nonfounders. Our software for splitting large pedigrees, PedCut, is available, free of charge, at the MGA Web site.Table 1.Genealogic Characteristics of 103 Patients with Late-Onset AD and Their RelativesCharacteristicValueaValues in parentheses indicate range or percentage.Complete genealogy: No. of family members4,645 No. of generations18 Average no. of consanguineous loops per patient71.7 (0–677) Average no. of meioses in a consanguineous loop9.9±1.2 (0–29) Mean inbreeding coefficient ×100.39±.73 (0–3.2) Average no. of lines of descent between a pair of patients141.7 (0–2,673) Average no. of meioses separating a pair of patients17.1±1.6 (0–34) Mean kinship coefficient ×100.18±1.06 (0–26.4)After clustering patients into subpedigrees: No. of subpedigrees35 No. of founders564 (46.0) No. of females630 (51.3) Mean pedigree size29.6 (18–75) Mean no. of generations7.5 (6–10) Mean no. of genotyped individuals per pedigree7.8 (2–14) Mean no. of patients per pedigree2.9 (2–6)a Values in parentheses indicate range or percentage. Open table in a new tab We further studied a series of 197 individuals who were not related withini 5 generations and were not related to the patients with AD. The average age of these people was 31.2±6.4 years; 51% were female. These individuals were evaluated with use of an extensive cognitive battery.48Sleegers K de Koning I Aulchenko YS van Rijn MJ Houben MP Croes EA van Swieten JC Oostra BA van Duijn CM Cerebrovascular risk factors do not contribute to genetic variance of cognitive function: the ERF study.Neurobiol Aging. 2007; 28: 735-741Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar In brief, the selection of tests included the 15-word test, the color word card of the Stroop Color Word test, part B of the Trail making test (TMTB), and the verbal fluency test. These tests were selected to target early cognitive problems related to AD. From the 15-word test, we derived three scores for further analysis—that is, learning (or working memory), delayed recall, and recognition. The verbal fluency test consists of two subdomains: semantic fluency and phonological fluency. The performance of each individual on each test was scored quantitatively. Power calculation showed that this sample has 80% power to detect a SNP explaining 4% of phenotypic variance with an α of .05. For all patients and their 170 first-degree relatives, DNA was extracted from peripheral leukocytes following a standard protocol.49Miller SA Dykes DD Polesky HF A simple salting out procedure for extracting DNA from human nucleated cells.Nucleic Acids Res. 1988; 16: 1215Crossref PubMed Scopus (17166) Google Scholar Elsewhere, mutations in the APP, PSEN1, and PSEN2 genes were excluded as AD-causing genes.36Sleegers K Roks G Theuns J Aulchenko YS Rademakers R Cruts M van Gool WA Van Broeckhoven C Heutink P Oostra BA et al.Familial clustering and genetic risk for dementia in a genetically isolated Dutch population.Brain. 2004; 127: 1641-1649Crossref PubMed Scopus (59) Google Scholar The APOE genotype was determined in all DNA samples by use of TaqMan allelic discrimination technology on an ABI Prism 7900HT Sequence Detection System with SDS version 2.1 (Applied Biosystems). Patients and their first-degree relatives underwent a full genome screen in two sequential experiments. Both screens were conducted using the same set of microsatellite markers, evenly spaced by ∼10 cM (ABI Prism Linkage Mapping Set MD-10 v. 2 and v. 2.5 [Applied Biosystems]). PCRs were performed according to the manufacturer’s specified conditions. PCR products were separately pooled and analyzed on ABI377 and ABI3100 automated sequencers (Applied Biosystems). Because the genome scan had been performed with different sequencing devices, the genetic data had to be merged. The genotypic data was pooled using Pool_STR-1.1, on the basis of the allele lengths and allele frequencies observed in each group.50Aulchenko YS Bertoli-Avella AM van Duijn CM A method for pooling alleles from different genotyping experiments.Ann Hum Genet. 2005; 69: 233-238Crossref PubMed Scopus (3) Google Scholar Two independent technicians read the results from the sequencers, and a third reader resolved the discordant results. Only the markers with a discordance proportion <5% were selected for further analysis (N=402). Genotyping errors leading to Mendelian inconsistencies were detected using PedCheck (Statgen).51O’Connell JR Weeks DE PedCheck: a program for identification of genotype incompatibilities in linkage analysis.Am J Hum Genet. 1998; 63: 259-266Abstract Full Text Full Text PDF PubMed Scopus (1806) Google Scholar Unlikely double-recombination events were detected using Merlin.52Abecasis GR Cherny SS Cookson WO Cardon LR Merlin—rapid analysis of dense genetic maps using sparse gene flow trees.Nat Genet. 2002; 30: 97-101Crossref PubMed Scopus (2693) Google Scholar Definitive genotyping errors and unlikely genotypes were rechecked using the data from the laboratory. Regions linked to late-onset AD were later fine typed by placing 45 additional microsatellite markers between those from the initial set, at a distance of 1–5 cM. SNPs in the linkage regions were selected from the 250K Nsp array of the GeneChip Human Mapping 500K Array Set (Affymetrix). Genomic DNA was extracted from whole-blood samples drawn at the baseline examination, with use of the salting-out method.49Miller SA Dykes DD Polesky HF A simple salting out procedure for extracting DNA from human nucleated cells.Nucleic Acids Res. 1988; 16: 1215Crossref PubMed Scopus (17166) Google Scholar The 250K Nsp array fro" @default.
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• W2023922415 title "A Genomewide Screen for Late-Onset Alzheimer Disease in a Genetically Isolated Dutch Population" @default.
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