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• W2093026964 abstract "Generalized vitiligo is a common, autoimmune, familial-clustering depigmentary disorder of the skin and hair that results from selective destruction of melanocytes. Generalized vitiligo is likely a heterogeneous disease, with five susceptibility loci reported so far—on chromosomes 1p31, 6p21, 7q, 8p, and 17p13—in white populations. To investigate vitiligo susceptibility loci in the Chinese population, we performed a genomewide linkage analysis in 57 multiplex Chinese families, each with at least two affected siblings, and we identified interesting linkage evidence on 1p36, 4q13-q21, 6p21-p22, 6q24-q25, 14q12-q13, and 22q12. Subsequently, to extract more linkage information, we investigated our initial genomewide linkage findings in a follow-up analysis of 49 new families and additional markers. Our initial genomewide linkage analysis and our subsequent follow-up analysis have identified a novel linkage to vitiligo on 4q13-q21, with highly significant linkage evidence (a nonparametic LOD score of 4.62 [P=.000003] and a heterogeneity LOD score of 4.01, under a recessive inheritance model), suggesting that 4q13-q21 likely harbors a major susceptibility locus for vitiligo in the Chinese population. We observed a minimal overlap between the linkage results of our current genomewide analysis in the Chinese population and the results of previous analyses in white populations, and we thus hypothesize that, as a polygenic disorder, vitiligo may be associated with great genetic heterogeneity and a substantial difference in its genetic basis between ethnic populations. Generalized vitiligo is a common, autoimmune, familial-clustering depigmentary disorder of the skin and hair that results from selective destruction of melanocytes. Generalized vitiligo is likely a heterogeneous disease, with five susceptibility loci reported so far—on chromosomes 1p31, 6p21, 7q, 8p, and 17p13—in white populations. To investigate vitiligo susceptibility loci in the Chinese population, we performed a genomewide linkage analysis in 57 multiplex Chinese families, each with at least two affected siblings, and we identified interesting linkage evidence on 1p36, 4q13-q21, 6p21-p22, 6q24-q25, 14q12-q13, and 22q12. Subsequently, to extract more linkage information, we investigated our initial genomewide linkage findings in a follow-up analysis of 49 new families and additional markers. Our initial genomewide linkage analysis and our subsequent follow-up analysis have identified a novel linkage to vitiligo on 4q13-q21, with highly significant linkage evidence (a nonparametic LOD score of 4.62 [P=.000003] and a heterogeneity LOD score of 4.01, under a recessive inheritance model), suggesting that 4q13-q21 likely harbors a major susceptibility locus for vitiligo in the Chinese population. We observed a minimal overlap between the linkage results of our current genomewide analysis in the Chinese population and the results of previous analyses in white populations, and we thus hypothesize that, as a polygenic disorder, vitiligo may be associated with great genetic heterogeneity and a substantial difference in its genetic basis between ethnic populations. Generalized vitiligo (MIM 193200) is a common acquired autoimmune disorder of skin and hair that results from selective destruction of melanocytes (Cho et al. Cho et al., 2000Cho S Kang HC Hahm JH Characteristics of vitiligo in Korean children.Pediatr Dermatol. 2000; 17: 189-193Crossref PubMed Scopus (78) Google Scholar). It is characterized by the appearance of sharply delimited patches of white skin overlying hair, oral mucosa, and occasionally the eyes, which are due to noninflammatory loss of pigment-forming melanocytes in affected areas. Vitiligo is associated with autoimmune disorders such as hypothyroidism, diabetes mellitus, chronic active hepatitis, pernicious anemia, and adrenal insufficiency (Kovacs Kovacs, 1998Kovacs SO Vitiligo.J Am Acad Dermatol. 1998; 38: 647-666Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar). The population prevalence of vitiligo ranges from 0.1% to 2% and shows a wide variability among ethnic groups (Bolognia et al. Bolognia et al., 1998Bolognia JL Nordlund JJ Ortonne J-P Vitiligo vulgaris.in: Nordlund JJ Boissy RE Hearing VJ King RA Ortonne J-P The pigmentary system. Oxford University Press, New York1998: 513-551Google Scholar; Hann and Nordlund Hann and Nordlund, 2000Hann S-K Nordlund J Vitiligo: a comprehensive monograph on basic and clinical science. Blackwell Science, Oxford, United Kingdom2000Crossref Scopus (1) Google Scholar). For example, whereas the estimated population prevalence of vitiligo is ∼0.38% for whites in the United States and northern Europe (Howitz et al. Howitz et al., 1977Howitz J Brodthagen H Schwartz M Thompsen K Prevalence of vitiligo: epidemiological survey of the Isle of Bornholm, Denmark.Arch Dermatol. 1977; 113: 47-52Crossref PubMed Scopus (226) Google Scholar), vitiligo affects only ∼0.19% of the population in China (Xu et al. Xu et al., 2002Xu YY Ye DQ Tong ZC Hao JH Jin J Shen SF Li CR Zhang XJ An epidemiological survey for four skin diseases in Anhui [In Chinese].Chin J Dermatol. 2002; 35: 406-407Google Scholar). Genetic risk for vitiligo is well supported by multiple lines of evidence. Vitiligo is frequently associated with familial clustering (Mehta et al. Mehta et al., 1973Mehta NR Shah KC Theodore C Vyas VP Patel AB Epidemiological study of vitiligo in Surat area.Indian J Med Res. 1973; 61: 145-154PubMed Google Scholar; Carnevale et al. Carnevale et al., 1980Carnevale A Zavala C Castillo VD Maldonado RR Tamayo L Analisis genetico de 127 families con vitiligo.Rev Invest Clin. 1980; 32: 37-41PubMed Google Scholar; Goudie et al. Goudie et al., 1983Goudie BM Wilkinson C Goudie RB A family study of vitiligo patterns.Scott Med J. 1983; 28: 338-342PubMed Google Scholar; Hafez et al. Hafez et al., 1983Hafez M Sharaf L Abd el-Nabi SM The genetics of vitiligo.Acta Derm Venereol. 1983; 63: 249-251PubMed Google Scholar; Das et al. Das et al., 1985Das SK Majumder PP Majumder TK Haldar B Studies on vitiligo. II. Familial aggregation and genetics.Genet Epidemiol. 1985; 2: 255-262Crossref PubMed Scopus (49) Google Scholar; Majumder et al. Majumder et al., 1993Majumder PP Nordlund JJ Nath SK Pattern of familial aggregation of vitiligo.Arch Dermatol. 1993; 129: 994-998Crossref PubMed Scopus (142) Google Scholar; Alkhateeb et al. Alkhateeb et al., 2003Alkhateeb A Fain PR Thody T Bennett DC Spritz RA Vitiligo and associated autoimmune diseases in Caucasian probands and their families.Pigment Cell Res. 2003; 16: 208-214Crossref PubMed Scopus (482) Google Scholar), and ∼20% of probands have at least one affected first-degree relative (Alkhateeb et al. Alkhateeb et al., 2003Alkhateeb A Fain PR Thody T Bennett DC Spritz RA Vitiligo and associated autoimmune diseases in Caucasian probands and their families.Pigment Cell Res. 2003; 16: 208-214Crossref PubMed Scopus (482) Google Scholar). The risk for first-degree relatives of patients with vitiligo to develop the disease is elevated by 7- to 10-fold (Nath et al. Nath et al., 1994Nath SK Majumder PP Nordlund JJ Genetic epidemiology of vitiligo: multilocus recessivity cross-validated.Am J Hum Genet. 1994; 55: 981-990PubMed Google Scholar) compared with the risk for the general population. Similarly, our recent study of the Chinese population indicated that ∼1.8% of patients’ first-degree relatives were affected with vitiligo, which was 9-fold higher than the prevalence rate in general population (Zhang et al. Zhang et al., 2004bZhang XJ Liu JB Gui JP Li M Xiong QG Wu HB Li JX Yang S Wang HY Gao M Yang J Yang Q Characteristics of genetic epidemiology and genetic models for vitiligo.J Am Acad Dermatol. 2004b; 51: 383-390Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). In addition, segregation analysis suggested that vitiligo is a multifactorial and polygenic disorder that likely results from multiple genetic and environmental factors (Arcos-Burgos et al. Arcos-Burgos et al., 2002Arcos-Burgos M Parodi E Salgar M Bedoya E Builes JJ Jaramillo D Ceballos G Uribe A Rivera N Rivera D Fonseca I Camargo M Palacio LG Vitiligo: complex segregation and linkage disequilibrium analyses with respect to microsatellite loci spanning the HLA.Hum Genet. 2002; 110: 334-342Crossref PubMed Scopus (68) Google Scholar; Alkhateeb et al. Alkhateeb et al., 2003Alkhateeb A Fain PR Thody T Bennett DC Spritz RA Vitiligo and associated autoimmune diseases in Caucasian probands and their families.Pigment Cell Res. 2003; 16: 208-214Crossref PubMed Scopus (482) Google Scholar; Zhang et al. Zhang et al., 2004bZhang XJ Liu JB Gui JP Li M Xiong QG Wu HB Li JX Yang S Wang HY Gao M Yang J Yang Q Characteristics of genetic epidemiology and genetic models for vitiligo.J Am Acad Dermatol. 2004b; 51: 383-390Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). However, no disease genes have been identified for vitiligo so far. Several genomewide linkage analyses of vitiligo have been performed in the past few years, and multiple linkages to vitiligo have been identified (Nath et al. Nath et al., 2001Nath SK Kelly JA Namjou B Lam T Bruner GR Scofield RH Aston CE Harley JB Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo-related systemic lupus erythematosus.Am J Hum Genet. 2001; 69: 1401-1406Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar; Alkhateeb et al. Alkhateeb et al., 2002Alkhateeb A Stetler GL Old W Talbert J Uhlhorn C Taylor M Fox A Miller C Dills DG Ridgway EC Bennett DC Fain PR Spritz RA Mapping of an autoimmunity susceptibility locus (AIS1) to chromosome 1p31.3-p32.2.Hum Mol Genet. 2002; 11: 661-667Crossref PubMed Scopus (103) Google Scholar; Fain et al. Fain et al., 2003Fain PR Gowan K LaBerge GS Alkhateeb A Stetler GL Talbert J Bennett DC Spritz RA A genomewide screen for generalized vitiligo: confirmation of AIS1 on chromosome 1p31 and evidence for additional susceptibility loci.Am J Hum Genet. 2003; 72: 1560-1564Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar; Spritz et al. Spritz et al., 2004Spritz RA Gowan K Bennett DC Fain PR Novel vitiligo susceptibility loci on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on chromosome 17, and their roles in an autoimmune diathesis.Am J Hum Genet. 2004; 74: 188-191Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). Using 16 European American pedigrees with cosegregation of systemic lupus erythematosus and vitiligo, Nath et al. (Nath et al., 2001Nath SK Kelly JA Namjou B Lam T Bruner GR Scofield RH Aston CE Harley JB Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo-related systemic lupus erythematosus.Am J Hum Genet. 2001; 69: 1401-1406Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar) performed the first genomewide linkage analysis of vitiligo and identified a significant linkage on 17p13. Shortly afterwards, Spritz and his colleagues performed a series of genomewide linkage analyses of vitiligo in white families. Their initial genomewide scan was done in a three-generation multiplex family with cosegregation of vitiligo and Hashimoto thyroiditis, and they identified a candidate gene with highly significant linkage at a locus (named “AIS1”) on chromosome 1p32.2-p31.3 (Alkhateeb et al. Alkhateeb et al., 2002Alkhateeb A Stetler GL Old W Talbert J Uhlhorn C Taylor M Fox A Miller C Dills DG Ridgway EC Bennett DC Fain PR Spritz RA Mapping of an autoimmunity susceptibility locus (AIS1) to chromosome 1p31.3-p32.2.Hum Mol Genet. 2002; 11: 661-667Crossref PubMed Scopus (103) Google Scholar). Subsequently, they performed a follow-up genomewide linkage analysis by studying 70 additional white families (Fain et al. Fain et al., 2003Fain PR Gowan K LaBerge GS Alkhateeb A Stetler GL Talbert J Bennett DC Spritz RA A genomewide screen for generalized vitiligo: confirmation of AIS1 on chromosome 1p31 and evidence for additional susceptibility loci.Am J Hum Genet. 2003; 72: 1560-1564Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Their follow-up analysis confirmed the original linkage finding at the AIS1 locus with highly significant linkage evidence (nonparametric LOD [NPL] score of 5.56) and identified additional linkage evidence on chromosomes 1, 7, 8, 11, 19, and 22. More recently, the group performed an extended genomewide linkage analysis, using 102 multiplex families (including the 70 families used in the previous genomewide scan) (Spritz et al. Spritz et al., 2004Spritz RA Gowan K Bennett DC Fain PR Novel vitiligo susceptibility loci on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on chromosome 17, and their roles in an autoimmune diathesis.Am J Hum Genet. 2004; 74: 188-191Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). The linkage results from the 102 families reinforced the strong support for the AIS1 locus and also confirmed the previously suggestive linkage findings on chromosomes 7q and 8p (AIS2 and AIS3). The study also provided supporting evidence for a disease locus on chromosome 17, which likely corresponds to the SLEV1 locus identified by Nath et al. (Nath et al., 2001Nath SK Kelly JA Namjou B Lam T Bruner GR Scofield RH Aston CE Harley JB Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo-related systemic lupus erythematosus.Am J Hum Genet. 2001; 69: 1401-1406Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). Interestingly, by stratifying their 102 families into autoimmunity- and nonautoimmunity-associated groups, Spritz and colleagues (Spritz et al., 2004Spritz RA Gowan K Bennett DC Fain PR Novel vitiligo susceptibility loci on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on chromosome 17, and their roles in an autoimmune diathesis.Am J Hum Genet. 2004; 74: 188-191Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar) found that, whereas the linkage evidence at the AIS1, AIS2, and SLEV1 loci was mainly from the autoimmunity-associated families, the evidence at the AIS3 locus was primarily from the nonautoimmunity-associated families, suggesting that generalized vitiligo might be divided into two distinct phenotypic subcategories that involve different disease loci or alleles. In addition to the genomewide linkage analyses, population-based association analyses were used to investigate several candidate genes for vitiligo—for example, CTLA-4 (Kemp et al. Kemp et al., 1999Kemp EH Ajjan RA Waterman EA Gawkrodger DJ Cork MJ Watson PF Weetman AP Analysis of a microsatellite polymorphism of the cytotoxic T-lymphocyte antigen-4 gene in patients with vitiligo.Br J Dermatol. 1999; 140: 73-78Crossref PubMed Scopus (52) Google Scholar; Blomhoff et al. Blomhoff et al., 2005Blomhoff A Helen Kemp E Gawkrodger DJ Weetman AP Husebye ES Akselsen HE Lie BA Undlien DE CTLA4 polymorphisms are associated with vitiligo, in patients with concomitant autoimmune diseases.Pigment Cell Res. 2005; 18: 55-58Crossref PubMed Scopus (55) Google Scholar), CAT and TAP1 (Casp et al. Casp et al., 2002Casp CB She JX McCormack WT Genetic association of the catalase gene (CAT) with vitiligo susceptibility.Pigment Cell Res. 2002; 15: 62-66Crossref PubMed Scopus (151) Google Scholar, Casp et al., 2003Casp CB She JX McCormack WT Genes of the LMP/TAP cluster are associated with the human autoimmune disease vitiligo.Genes Immun. 2003; 4: 492-499Crossref PubMed Scopus (55) Google Scholar), MC1R and ASIP (Na et al. Na et al., 2003Na GY Lee KH Kim MK Lee SJ Kim do W Kim JC Polymorphisms in the melanocortin-1 receptor (MC1R) and agouti signaling protein (ASIP) genes in Korean vitiligo patients.Pigment Cell Res. 2003; 16: 383-387Crossref PubMed Scopus (28) Google Scholar), ACE (Jin et al. Jin et al., 2004Jin SY Park HH Li GZ Lee HJ Hong MS Hong SJ Park HK Chung JH Lee MH Association of angiotensin converting enzyme gene I/D polymorphism of vitiligo in Korean population.Pigment Cell Res. 2004; 17: 84-86Crossref PubMed Scopus (47) Google Scholar), and HLA (Zamani et al. Zamani et al., 2001Zamani M Spaepen M Sghar SS Huang C Westerhof W Nieuweboer-Krobotova L Cassiman JJ Linkage and association of HLA class II genes with vitiligo in a Dutch population.Br J Dermatol. 2001; 145: 90-94Crossref PubMed Scopus (71) Google Scholar; Tastan et al. Tastan et al., 2004Tastan HB Akar A Orkunoglu FE Arca E Inal A Association of HLA class I antigens and HLA class II alleles with vitiligo in a Turkish population.Pigment Cell Res. 2004; 17: 181-184Crossref PubMed Scopus (52) Google Scholar; Zhang et al. Zhang et al., 2004aZhang XJ Liu HS Liang YH Sun LD Wang JY Yang S Liu JB Gao M He PP Cui Y Yang Q Association of HLA class I alleles with vitiligo in Chinese Hans.J Dermatol Sci. 2004a; 35: 165-168Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). Here, we report the first genomewide linkage analysis of vitiligo in a Chinese population. Our family collection includes 106 Chinese multiplex families, each with at least two siblings affected with generalized vitiligo (table 1). All the families were recruited by experienced dermatologists from the Department of Dermatology at First Affiliated Hospital of Anhui Medical University at Hefei, Anhui, China, and from the Vitiligo Clinic of the Railway Hospital at Xiangfan, Hubei, China. The diagnosis of generalized vitiligo was made on the basis of the patient’s history and the presence of typical clinical features (discrete, well-circumscribed depigmented patches). Phenotypes were carefully determined by history, lesion maps, and, in most cases, physical examination and/or photographs. Any individual whose phenotype was questionable was excluded from the study. Only patients with clear signs of acquired patches on the extremities, trunk, genitalia, central face, or other areas were scored as affected. The mean age at onset of the 286 affected individuals (148 male [51.7%] and 138 female [48.3%]) from the 106 families was 18.6 years (range 1–63 years). Of the 106 families, 57 families were used in an initial genomewide linkage analysis, and 49 families were used in a follow-up linkage analysis in which the initial linkage findings from the genomewide scan were further investigated by use of dense marker coverage (table 1). For each family, blood samples were collected from all affected individuals, their parents, and additional family members connecting affected individuals. Among the 106 families, blood samples were collected from both parents in 81 families and from one parent in 17 families. Eight families were missing samples from both parents of affected individuals. When samples from one or both parents of an affected individual were unavailable, a blood sample was collected from at least one additional unaffected sibling. Informed consent was obtained from each recruited subject. The study was approved by the Ethical Committee of the Chinese National Human Genome Center at Shanghai.Table 1Summary of Analyses of FamiliesTotal No. ofNo. of Families by No. of Affecteds (Total No. of Affecteds)AnalysisFamiliesAffectedsTwo AffectedsThree AffectedsFour or More AffectedsInitial genomewide scan5717223 (46)17 (51)17 (75)Follow-up4911435 (70)12 (36)2 (8)Combined10628658 (116)29 (87)19 (83) Open table in a new tab Genomic DNA was extracted from whole blood by use of a simple salting-out procedure, as described elsewhere (Miller et al. Miller et al., 1988Miller S Dykes D Polesky H A simple salting out procedure for extraction of high molecular weight DNA from human nucleated cells.Nucl Acids Res. 1988; 16: 1215Crossref PubMed Scopus (17178) Google Scholar). We performed a genomewide linkage analysis of vitiligo by genotyping 382 microsatellite markers from the ABI Prism Linkage Mapping Set (version 2) in 57 families. Average marker spacing is 8.85 cM (range 1–19 cM), and average marker information content is 0.72, on the basis of genotypes from the 57 families. All the marker positions were based on an interpolated genetic map that incorporates the information from a physical map (build 34.3) and from published deCODE and Marshfield genetic maps (see David Duffy’s QIMR Homepage). All the markers were genotyped in multiplex PCR, in accordance with the manufacturer's guidelines (Applied Biosystems). Before being used in linkage analysis, all genotyping data were subjected to quality checking by use of the programs PedCheck (O’Connell and Weeks O’Connell and Weeks, 1998O’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) and MERLIN (Abecasis et al. Abecasis et al., 2002Abecasis 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 (2697) Google Scholar). Problematic genotypes either were corrected by rechecking original allele callings or were removed if allele status could not be reliably determined. Both nonparametric and parametric linkage analyses were performed using the program GENEHUNTER 2.1 (Kruglyak et al. Kruglyak et al., 1996Kruglyak L Daly MJ Reeve-Daly, MP Lander ES Parametric and nonparametric linkage analysis: a unified multipoint approach.Am J Hum Genet. 1996; 58: 1347-1363PubMed Google Scholar). For nonparametric analysis, the NPL score was calculated using the Sall statistic to capture the information about allele sharing between all affected individuals in a pedigree. For parametric analysis, the heterogeneity LOD (HLOD) score was calculated by assuming a dominant or recessive inheritance of the disease allele and a disease-allele frequency of 0.01, consistent with the population prevalence of 0.19% in China (Xu et al. Xu et al., 2002Xu YY Ye DQ Tong ZC Hao JH Jin J Shen SF Li CR Zhang XJ An epidemiological survey for four skin diseases in Anhui [In Chinese].Chin J Dermatol. 2002; 35: 406-407Google Scholar). Moreover, to reduce the impact of the nonpenetrant disease allele on linkage analysis, genomewide parametric analysis was performed by using an “affecteds-only” approach, in which all normal individuals were treated as “unknown” instead of “unaffected,” and by assuming a simple genetic model with high penetrance (0.99) and very low phenocopy rates (0.001). Marker-allele frequency was estimated on the basis of founders’ genotypes of either 57 families (for the genomewide analysis) or 106 families (for the follow-up analysis) by use of the program Linkage 5.10 (Lathrop and Lalouel Lathrop and Lalouel, 1984Lathrop GM Lalouel JM Easy calculations of lod scores and genetic risks on small computers.Am J Hum Genet. 1984; 36: 460-465PubMed Google Scholar). Multipoint nonparametric analysis identified linkage signals on 1p36, 4q13-q21, 6p21-p22, 6q24-q25, 14q12-q13, and 22q12 (fig. 1). Of these, the highest NPL score was 3.05 (P=.0017), identified at the marker interval D6S308–D6S441 on 6q24-q25; this was followed by NPL scores of 2.94 (P=.0021) at the marker interval D4S1592–D4S1534 on 4q13-q21, 2.87 (P=.0023) at the marker interval D22S280–D22S283 on 22q12, 2.83 (P=.0026) at the marker interval D14S275–D14S70 on 14q12-13, 2.68 (P=.0044) at the marker interval D6S422–D6S273 on 6p21-p22, and 2.67 (P=.0045) at the marker interval D1S234–D1S2885 on 1p36. Multipoint parametric linkage analysis under a recessive model of inheritance identified suggestive evidence for linkage (HLOD score of 1.86 or higher) (Lander and Kruglyak Lander and Kruglyak, 1995Lander E Kruglyak L Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results.Nat Genet. 1995; 11: 241-247Crossref PubMed Scopus (4381) Google Scholar) on 4q12-q13, 5p15, 6q24-q25, and 8q24 (fig. 1). The most significant HLOD score under a recessive model was 2.99 (α=36%) at the marker interval D6S308–D6S441, which was followed by multipoint HLOD scores of 2.48 (α=34%) at the marker interval D5S1981–D5S406, 2.15 (α=38%) at the marker interval D8S284–D8S272, and 1.94 (α=28%) at the marker interval D4S1592–D4S392. Under a dominant model of inheritance, multipoint parametric analysis identified suggestive linkage evidence on 2q13, 6p21-p22, 14q12-q13, and 22q12 (fig. 1). The highest HLOD score of 2.28 (α=59%) was identified at marker D2S160, which was followed by HLOD scores of 2.26 (α=37%) at the marker interval D6S422–D6S273, 2.15 (α=48%) at the marker interval D14S275–D14S70, and 2.07 (α=46%) at the marker interval D6S308–D6S441. For both nonparametric and parametric genomewide linkage analyses, two-point LOD scores (data not shown) were consistent with the multipoint LOD scores but were generally lower. Our genomewide linkage analysis of vitiligo in the 57 Chinese families identified interesting linkage signals in six genomic regions. The most significant evidence for linkage was on 6q24-q25 and was supported by a maximum multipoint NPL score of 3.05 and a recessive HLOD score of 2.99. The second-most significant evidence was on 4q13-q21, with a maximum multipoint NPL score of 2.94 and a recessive HLOD score of 1.94, which was followed by linkage evidence on 6p21-p22, with a maximum multipoint NPL score of 2.67 and a dominant HLOD score of 2.26. Linkage evidence was also identified on 1p36, 14q12-q13, and 22q12, but the evidence was less significant (table 2). To further investigate these initial linkage findings, we analyzed an additional 49 Chinese families recruited from the same clinics in a follow-up analysis in which additional markers were genotyped to extract more linkage information. Instead of using the “affecteds-only” approach, we performed the follow-up parametric analysis of the initial linkage findings by assuming a disease-allele frequency of 0.01, a variable penetrance rate (range 0.5–0.99), and a fixed phenotype rate of 0.001 and by using the inheritance model under which the initial linkage evidence was identified in the genomewide analysis. Changing the penetrance rate made almost no impact on HLOD score results (data not shown); therefore, only HLOD scores under the penetrance rate of 0.99 were reported.Table 2Summary of the Multipoint LOD Scores from the Initial Genomewide and Follow-up Linkage AnalysesInitial AnalysisaPerformed by analyzing 382 microsatellite markers in 57 multiplex Chinese families.Follow-Up AnalysisbPerformed by analyzing various numbers of markers in 49 multiplex Chinese families.Combined AnalysiscPerformed by analyzing various numbers of markers in 106 multiplex Chinese families.ChromosomeMarker or IntervalNPLPHLODα (%)NPLPHLODα (%)NPLPHLODα (%)Genetic ModeldRec = recessive inheritance; Dom = dominant inheritance.1p36D1S2674–D1S28852.67.00451.0821.98.16.094.52.37.00931.1711 Rec4q13-q21D4S1592–D4S15342.94.00211.94284.29.000012.74354.62.0000034.0131 Rec6p21-p22D6S289–D6S2912.68.00442.26372.17.0161.32453.16.000922.1432 Dom6q24-q25D6S308–D6S4413.05.00172.99361.27.11.31112.98.00161.3716 Rec14q12-q13D14S702.83.00262.1548.048.48002.17.0141.5134 Dom22q12D22S280–D22S2832.87.00231.5533.47.32.0066.0381.75.039.7219 Doma Performed by analyzing 382 microsatellite markers in 57 multiplex Chinese families.b Performed by analyzing various numbers of markers in 49 multiplex Chinese families.c Performed by analyzing various numbers of markers in 106 multiplex Chinese families.d Rec = recessive inheritance; Dom = dominant inheritance. Open table in a new tab The initial linkage finding on 4q13-q21 was further investigated by genotyping 12 new and 5 original microsatellite markers in 106 families, which increased the marker density to an average marker spacing of 3.3 cM. We first performed a joint linkage analysis of 106 families, including 57 original and 49 new families. Multipoint linkage analysis of 17 markers yielded a maximum NPL score of 4.62 (P=.000003) at the marker interval D4S392–D4S3042 and a maximum HLOD score of 4.01 (α=31%) at the adjacent marker interval D4S3042–D4S2947, under a recessive model of inheritance (fig. 2 and table 2). The multipoint LOD score results were supported by a two-point analysis that yielded a maximum two-point NPL score of 4.53 (P=.000004) and a recessive HLOD score of 5.97 (α=42%) at the marker locus D4S392. Both nonparametric and parametric LOD scores of the joint linkage analysis of the 106 families on 4q13-q21 surpassed the suggested genomewide criteria for significant linkage evidence (Lander and Kruglyak Lander and Kruglyak, 1995Lander E Kruglyak L Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results.Nat Genet. 1995; 11: 241-247Crossref PubMed Scopus (4381) Google Scholar). In addition, we also performed an independent linkage analysis of the same 17 markers in 49 new families by using the same genetic model. The linkage analysis of the 49 new families provided independent supporting evidence for linkage, yielding a multipoint NPL score of 4.29 (P=.00001) and an HLOD score of 2.74 (α=35%) at the same genetic position. Therefore, our initial genomewide and subsequent fine-mapping linkage analyses have identified a novel linkage to vitiligo on 4q13-q21. The two-point HLOD score at D4S392 is considerably higher than the multipoint HLOD score. This is not unexpected, because two-point linkage analysis is known to be more prone than multipoint analysis to inflated or deflated LOD scores. Marker information content at the D4S392 locus is 0.61 in our families, which is much lower than the marker information content of ∼0.9 that was achieved in our multipoint linkage analysis (fig. 2). A less informative marker, which is more likely to be present in two-point analysis than in multipoint analys" @default.
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• W2093026964 title "A Novel Linkage to Generalized Vitiligo on 4q13-q21 Identified in a Genomewide Linkage Analysis of Chinese Families" @default.
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