Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo-related systemic lupus erythematosus

Both systemic lupus erythematosus (SLE) and vitiligo are autoimmune disorders that have strong evidence of complex genetic contributions to their etiology, but, to date, efforts using genetic linkage to find the susceptibility genes for either phenotype have met with limited success. Since autoimmune diseases are thought to share at least some of their genetic origins, and since only a small minority (16 of 92) of the European-American pedigrees multiplex for SLE in our collection have one or more affected members with vitiligo, we hypothesized that these pedigrees might be more genetically homogeneous at loci important to both SLE and vitiligo and, hence, have increased power for detection of linkage. We therefore evaluated genomewide microsatellite-marker-scan data for markers at an average marker density of approximately 11 cM in these 16 European-American pedigrees and identified a significant linkage at 17p13, where the maximum multipoint parametric LOD score was 3.64 (P<4.3x10(-5)) and the nonparametric linkage score was 4.02 (P<2.8x10(-5)), respectively. The segregation behavior of this linkage suggests a recessive mode of inheritance with a virtually homogeneous genetic effect in these 16 pedigrees. These results support the hypotheses that SLE and vitiligo may share important genetic effects and that sampling on the basis of clinical covariates dramatically improves power to identify genetic effects.     

A novel linkage to generalized vitiligo on 4q13-q21 identified in a genomewide linkage analysis of Chinese families

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.     

Recent progress in the genetics of generalized vitiligo

Vitiligo is an acquired disease characterized principally by patchy depigmentation of skin and overlying hair. Generalized vitiligo (GV), the predominant form of the disorder, results from autoimmune loss of melanocytes from affected regions. GV is a “complex trait”, inherited in a non-Mendelian polygenic, multifactorial manner. GV is epidemiologically associated with other autoimmune diseases, both in GV patients and in their close relatives, suggesting that shared genes underlie susceptibility to this group of diseases. Early candidate gene association studies yielded a few successes, such as PTPN22, but most such reports now appear to be false-positives. Subsequent genomewide linkage studies identified NLRPI and XBPI, apparent true GV susceptibility genes involved in immune regulation, and recent genome-wide association studies (GWAS) of GV in Caucasian and Chinese populations have yielded a large number of additional validated GV susceptibility genes.Together, these genes highlight biological systems and pathways that reach from the immune cells to the melanocyte, and provide insights into both disease pathogenesis and potential new targets for both treatment and even prevention of GV and other autoimmune diseases in genetically susceptible individuals.     

Genomewide scan in families with schizophrenia from the founder population of Afrikaners reveals evidence for linkage and uniparental disomy on chromosome 1

We report on our initial genetic linkage studies of schizophrenia in the genetically isolated population of the Afrikaners from South Africa. A 10-cM genomewide scan was performed on 143 small families, 34 of which were informative for linkage. Using both nonparametric and parametric linkage analyses, we obtained evidence for a small number of disease loci on chromosomes 1, 9, and 13. These results suggest that few genes of substantial effect exist for schizophrenia in the Afrikaner population, consistent with our previous genealogical tracing studies. The locus on chromosome 1 reached genomewide significance levels (nonparametric LOD score of 3.30 at marker D1S1612, corresponding to an empirical P value of.012) and represents a novel susceptibility locus for schizophrenia. In addition to providing evidence for linkage for chromosome 1, we also identified a proband with a uniparental disomy (UPD) of the entire chromosome 1. This is the first time a UPD has been described in a patient with schizophrenia, lending further support to involvement of chromosome 1 in schizophrenia susceptibility in the Afrikaners.     

A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases

Rheumatoid arthritis (RA) is an autoimmune/inflammatory disorder with a complex genetic component. We report the first major genomewide screen of multiplex families with RA gathered in the United States. The North American Rheumatoid Arthritis Consortium, using well-defined clinical criteria, has collected 257 families containing 301 affected sibling pairs with RA. A genome screen for allele sharing was performed, using 379 microsatellite markers. A nonparametric analysis using SIBPAL confirmed linkage of the HLA locus to RA (P < .00005), with lambdaHLA = 1.79. However, the analysis also revealed a number of non-HLA loci on chromosomes 1 (D1S235), 4 (D4S1647), 12 (D12S373), 16 (D16S403), and 17 (D17S1301), with evidence for linkage at a significance level of P<.005. Analysis of X-linked markers using the MLOD method from ASPEX also suggests linkage to the telomeric marker DXS6807. Stratifying the families into white or seropositive subgroups revealed some additional markers that showed improvement in significance over the full data set. Several of the regions that showed evidence for nominal significance (P < .05) in our data set had previously been implicated in RA (D16S516 and D17S1301) or in other diseases of an autoimmune nature, including systemic lupus erythematosus (D1S235), inflammatory bowel disease (D4S1647, D5S1462, and D16S516), multiple sclerosis (D12S1052), and ankylosing spondylitis (D16S516). Therefore, genes in the HLA complex play a major role in RA susceptibility, but several other regions also contribute significantly to overall genetic risk.     

HLA class II haplotype DRB1*04-DQB1*0301 contributes to risk of familial generalized vitiligo and early disease onset

Generalized vitiligo is a common autoimmune disorder characterized by white patches of skin and overlying hair caused by loss of pigment-forming melanocytes from involved areas. Familial clustering of vitiligo is not uncommon, and patients and their relatives are at increased risk for a specific complex of other autoimmune diseases. Compared with sporadic vitiligo, familial vitiligo is characterized by earlier disease onset and greater risk and broader repertoire of autoimmunity, suggesting a stronger genetic component, and perhaps stronger associations with specific alleles. To determine whether the major histocompatibility complex (MHC) contributes to the familial clustering of vitiligo and vitiligo-associated autoimmune/autoinflammatory diseases, we performed case-control and family-based association analyses of HLA class II-DRB1 and -DQB1 alleles and haplotypes in affected probands and their parents from 76 European-American Caucasian families with familial vitiligo. Affected probands showed a significantly increased frequency of DRB1*04-DQB1*0301 and a significantly decreased frequency of DRB1*15-DQB1*0602 compared with a large sample of reference chromosomes. Family-based association analyses confirmed these results. Probands with DRB1*04-DQB1*0301 developed vitiligo an average of 13.32 yr earlier than probands with DRB1*15-DQB1*0602. Overall, our results indicate that specific MHC-linked genetic variation contributes to risk of familial vitiligo, although HLA does not completely explain familial clustering of vitiligo-associated autoimmune/autoinflammatory diseases.     

Genomewide linkage screen for Waldenstrom macroglobulinemia susceptibility loci in high-risk families

Waldenstrom macroglobulinemia (WM), a distinctive subtype of non-Hodgkin lymphoma that features overproduction of immunoglobulin M (IgM), clearly has a familial component; however, no susceptibility genes have yet been identified. We performed a genomewide linkage analysis in 11 high-risk families with WM that were informative for linkage, for a total of 122 individuals with DNA samples, including 34 patients with WM and 10 patients with IgM monoclonal gammopathy of undetermined significance (IgM MGUS). We genotyped 1,058 microsatellite markers (average spacing 3.5 cM), performed both nonparametric and parametric linkage analysis, and computed both two-point and multipoint linkage statistics. The strongest evidence of linkage was found on chromosomes 1q and 4q when patients with WM and with IgM MGUS were both considered affected; nonparametric linkage scores were 2.5 (P=.0089) and 3.1 (P=.004), respectively. Other locations suggestive of linkage were found on chromosomes 3 and 6. Results of two-locus linkage analysis were consistent with independent effects. The findings from this first linkage analysis of families at high risk for WM represent important progress toward identifying gene(s) that modulate susceptibility to WM and toward understanding its complex etiology.     

HLA class II haplotype DRB1*04–DQB1*0301 contributes to risk of familial generalized vitiligo and early disease onset

Generalized vitiligo is a common autoimmune disorder characterized by white patches of skin and overlying hair caused by loss of pigment‐forming melanocytes from involved areas. Familial clustering of vitiligo is not uncommon, and patients and their relatives are at increased risk for a specific complex of other autoimmune diseases. Compared with sporadic vitiligo, familial vitiligo is characterized by earlier disease onset and greater risk and broader repertoire of autoimmunity, suggesting a stronger genetic component, and perhaps stronger associations with specific alleles. To determine whether the major histocompatibility complex (MHC) contributes to the familial clustering of vitiligo and vitiligo‐associated autoimmune/autoinflammatory diseases, we performed case–control and family‐based association analyses of HLA class II‐DRB1 and ‐DQB1 alleles and haplotypes in affected probands and their parents from 76 European‐American Caucasian families with familial vitiligo. Affected probands showed a significantly increased frequency of DRB1*04–DQB1*0301 and a significantly decreased frequency of DRB1*15–DQB1*0602 compared with a large sample of reference chromosomes. Family‐based association analyses confirmed these results. Probands with DRB1*04–DQB1*0301 developed vitiligo an average of 13.32 yr earlier than probands with DRB1*15–DQB1*0602. Overall, our results indicate that specific MHC‐linked genetic variation contributes to risk of familial vitiligo, although HLA does not completely explain familial clustering of vitiligo‐associated autoimmune/autoinflammatory diseases.     

Linkage at 12q24 with systemic lupus erythematosus (SLE) is established and confirmed in Hispanic and European American families

Systemic lupus erythematosus (SLE) is a chronic, complex, and systemic human autoimmune disease, with both an environmental component and a heritable predisposition. Clinical studies, reinforced by epidemiology and genetics, show impressive variation in disease severity, expression, prevalence, and incidence by ethnicity and sex. To identify the novel SLE susceptibility loci, we performed a genomewide scan with 318 markers on 37 multiplex Hispanic families, using a nonparametric penetrance-independent affected-only allele-sharing method. Three chromosomal regions (12q24, 16p13, and 16q12-21) exceeded our predetermined threshold (Zlr>2.32; nominal P<.01) for further evaluation. Suspected linkages at 12q24, 16p13, and 16q12-21 were tested in an independent data set consisting of 92 European American (EA-1) and 55 African American (AA) families. The linkage at 12q24 was replicated in EA-1 (Zlr=3.06; P=.001) but not in AA (Zlr=0.37; P=.35). Although neither the 16p13 nor the 16q12-21 was confirmed in EA-1 or AA, the suggestive linkage (Zlr=3.06; P=.001) at 16q12-21 is sufficient to confirm the significant linkage, reported elsewhere, at this location. The evidence for linkage at 12q24 in the 129 combined (Hispanic and EA-1) families exceeded the threshold for genomewide significance (Zlr=4.39; P=5.7x10-6; nonparametric LOD=4.19). Parametric linkage analyses suggested a low-penetrance, dominant model (LOD=3.72). To confirm the linkage effect at 12q24, we performed linkage analysis in another set of 82 independent European American families (EA-2). The evidence for linkage was confirmed (Zlr=2.11; P=.017). Therefore, our results have detected, established, and confirmed the existence of a novel SLE susceptibility locus at 12q24 (designated "SLEB4") that may cause lupus, especially in Hispanic and European American families.     

Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative

We conducted genomewide linkage analyses on 1,152 individuals from 250 families segregating for bipolar disorder and related affective illnesses. These pedigrees were ascertained at 10 sites in the United States, through a proband with bipolar I affective disorder and a sibling with bipolar I or schizoaffective disorder, bipolar type. Uniform methods of ascertainment and assessment were used at all sites. A 9-cM screen was performed by use of 391 markers, with an average heterozygosity of 0.76. Multipoint, nonparametric linkage analyses were conducted in affected relative pairs. Additionally, simulation analyses were performed to determine genomewide significance levels for this study. Three hierarchical models of affection were analyzed. Significant evidence for linkage (genomewide P<.05) was found on chromosome 17q, with a peak maximum LOD score of 3.63, at the marker D17S928, and on chromosome 6q, with a peak maximum LOD score of 3.61, near the marker D6S1021. These loci met both standard and simulation-based criteria for genomewide significance. Suggestive evidence of linkage was observed in three other regions (genomewide P<.10), on chromosomes 2p, 3q, and 8q. This study, which is based on the largest linkage sample for bipolar disorder analyzed to date, indicates that several genes contribute to bipolar disorder.     

Linkage analyses at the chromosome 1 loci 1q24-25 (HPC1), 1q42.2-43 (PCAP), and 1p36 (CAPB) in families with hereditary prostate cancer

Recent studies suggest that hereditary prostate cancer (PRCA) is a complex disease, involving multiple susceptibility genes and variable phenotypic expression. Through linkage analysis, potential prostate cancer susceptibility loci have been mapped to 3 regions on chromosome 1. To investigate the reported linkage to these regions, we conducted linkage studies on 144 PRCA families by using microsatellite markers in regions 1q24-25 (HPC1) and 1q42.2-43 (PCAP). We also examined the 1p36 (CAPB) region in 13 PRCA families with at least one case of brain cancer. No significant evidence of linkage to the HPC1 or PCAP region was found when the entire data set was analyzed. However, weak evidence for linkage to HPC1 was observed in the subset of families with male-to-male transmission (n=102; maximum multipoint nonparametric linkage [NPL] 1.99, P=.03). Weak evidence for linkage with heterogeneity within this subset was also observed (HLOD 1.21, P=.02), with approximately 20% of families linked. Although not statistically significant, suggestive evidence for linkage to PCAP was observed for the families (n=21) that met the three criteria of male-to-male transmission, average age of diagnosis <66 years, and >/=5 affected individuals (maximum multipoint NPL 1.45, P=.08). There was no evidence for linkage to CAPB in the brain cancer-prostate cancer subset. These results strengthen the argument that prostate cancer is a heterogeneous disease and that multiple genetic and environmental factors may be important for its etiology.     

A genomewide scan for early-onset coronary artery disease in 438 families: the GENECARD Study

A family history of coronary artery disease (CAD), especially when the disease occurs at a young age, is a potent risk factor for CAD. DNA collection in families in which two or more siblings are affected at an early age allows identification of genetic factors for CAD by linkage analysis. We performed a genomewide scan in 1,168 individuals from 438 families, including 493 affected sibling pairs with documented onset of CAD before 51 years of age in men and before 56 years of age in women. We prospectively defined three phenotypic subsets of families: (1) acute coronary syndrome in two or more siblings; (2) absence of type 2 diabetes in all affected siblings; and (3) atherogenic dyslipidemia in any one sibling. Genotypes were analyzed for 395 microsatellite markers. Regions were defined as providing evidence for linkage if they provided parametric two-point LOD scores >1.5, together with nonparametric multipoint LOD scores >1.0. Regions on chromosomes 3q13 (multipoint LOD = 3.3; empirical P value <.001) and 5q31 (multipoint LOD = 1.4; empirical P value <.081) met these criteria in the entire data set, and regions on chromosomes 1q25, 3q13, 7p14, and 19p13 met these criteria in one or more of the subsets. Two regions, 3q13 and 1q25, met the criteria for genomewide significance. We have identified a region on chromosome 3q13 that is linked to early-onset CAD, as well as additional regions of interest that will require further analysis. These data provide initial areas of the human genome where further investigation may reveal susceptibility genes for early-onset CAD.     

Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families

Generalized vitiligo is an autoimmune disorder characterized by acquired white patches of skin and overlying hair, the result of loss of melanocytes from involved areas. The most common disorder of pigmentation, vitiligo occurs with a frequency of 0.1-2.0% in various populations. Family clustering of cases is not uncommon, in a non-Mendelian pattern suggestive of multifactorial, polygenic inheritance. We surveyed 2624 vitiligo probands from North America and the UK regarding clinical characteristics, familial involvement, and association with other autoimmune disorders, the largest such survey ever performed. More than 83% of probands were Caucasians, and the frequency of vitiligo appeared approximately equal in males and females. The frequency of vitiligo in probands' siblings was 6.1%, about 18 times the population frequency, suggesting a major genetic component in disease pathogenesis. Nevertheless, the concordance of vitiligo in monozygotic twins was only 23%, indicating that a non-genetic component also plays an important role. Probands with earlier disease onset tended to have more relatives affected with vitiligo, suggesting a greater genetic component in early onset families. The frequencies of six autoimmune disorders were significantly elevated in vitiligo probands and their first-degree relatives: vitiligo itself, autoimmune thyroid disease (particularly hypothyroidism), pernicious anaemia, Addison's disease, systemic lupus erythematosus, and probably inflammatory bowel disease. These associations indicate that vitiligo shares common genetic aetiologic links with these other autoimmune disorders. These results suggest that genomic analysis of families with generalized vitiligo and this specific constellation of associated autoimmune disorders will be important to identify the mechanisms of genetic susceptibility to autoimmunity.     

Early disease onset and increased risk of other autoimmune diseases in familial generalized vitiligo

Generalized vitiligo is an autoimmune disorder in which acquired white patches of skin and overlying hair result from autoimmune loss of melanocytes from involved areas. Although usually sporadic, family clustering of vitiligo may occur, in a non-Mendelian pattern typical of multifactorial, polygenic inheritance. Sporadic vitiligo is associated with autoimmune thyroid disease, pernicious anemia, Addison's disease, and lupus; these same disorders occur at increased frequency in patients' first-degree relatives. Here, we studied 133 'multiplex' generalized vitiligo families, with multiple affected family members. The age of onset of vitiligo is earlier in these 'multiplex' families than in patients with sporadic vitiligo. Affected members of the multiplex vitiligo families have elevated frequencies of autoimmune thyroid disease, rheumatoid arthritis, psoriasis, adult-onset insulin-dependent diabetes mellitus, pernicious anemia, and Addison's disease. Probands' unaffected siblings have elevated frequencies of most of these same autoimmune diseases, particularly if the proband had non-vitiligo autoimmune disease. Familial generalized vitiligo is thus characterized by earlier disease onset and a broader repertoire of associated autoimmune diseases than sporadic vitiligo. This mostly likely reflects a greater inherited genetic component of autoimmune susceptibility in these families. These findings have important implications for autoimmune disease surveillance in families in which multiple members are affected with vitiligo.     

Evidence for a Susceptibility Gene for Anorexia Nervosa on Chromosome 1

Eating disorders, such as anorexia nervosa (AN), have a significant genetic component. In the current study, a genomewide linkage analysis of 192 families with at least one affected relative pair with AN and related eating disorders, including bulimia nervosa, was performed, resulting in only modest evidence for linkage, with the highest nonparametric linkage (NPL) score, 1.80, at marker D4S2367 on chromosome 4. Since the reduction of sample heterogeneity would increase power to detect linkage, we performed linkage analysis in a subset (n=37) of families in which at least two affected relatives had diagnoses of restricting AN, a clinically defined subtype of AN characterized by severe limitation of food intake without the presence of binge-eating or purging behavior. When we limited the linkage analysis to this clinically more homogeneous subgroup, the highest multipoint NPL score observed was 3.03, at marker D1S3721 on chromosome 1p. The genotyping of additional markers in this region led to a peak multipoint NPL score of 3.45, thereby providing suggestive evidence for the presence of an AN-susceptibility locus on chromosome 1p.     

Whole-genome screening in ankylosing spondylitis: evidence of non-MHC genetic-susceptibility loci

Ankylosing spondylitis (AS) is a common inflammatory arthritis predominantly affecting the axial skeleton. Susceptibility to the disease is thought to be oligogenic. To identify the genes involved, we have performed a genomewide scan in 185 families containing 255 affected sibling pairs. Two-point and multipoint nonparametric linkage analysis was performed. Regions were identified showing "suggestive" or stronger linkage with the disease on chromosomes 1p, 2q, 6p, 9q, 10q, 16q, and 19q. The MHC locus was identified as encoding the greatest component of susceptibility, with an overall LOD score of 15.6. The strongest non-MHC linkage lies on chromosome 16q (overall LOD score 4.7). These results strongly support the presence of non-MHC genetic-susceptibility factors in AS and point to their likely locations.     

The genetics of generalized vitiligo and associated autoimmune diseases

Vitiligo is an acquired disorder in which patches of depigmented skin and often overlying hair, and mucous membranes, are the result of progressive autoimmune loss of melanocytes from the involved areas. Considered the most common pigmentary disorder, vitiligo involves complex interaction of environmental and genetic factors that ultimately contribute to melanocyte destruction, resulting in the characteristic depigmented lesions. In the past few years, studies of the genetic epidemiology of vitiligo have led to the recognition that generalized vitiligo is part of a broader autoimmune disease diathesis. Attempts to identify genes involved in susceptibility to generalized vitiligo have involved gene expression studies, genetic association studies of candidate genes, and genome-wide linkage analyses to discover new genes. These studies have begun to yield results that shed light on the mechanisms of vitiligo pathogenesis. It is anticipated that the discovery of biological pathways of vitiligo pathogenesis will provide novel targets for future approaches to the treatment and prevention of vitiligo and its associated autoimmune diseases.     

A high-density screen for linkage in multiple sclerosis

To provide a definitive linkage map for multiple sclerosis, we have genotyped the Illumina BeadArray linkage mapping panel (version 4) in a data set of 730 multiplex families of Northern European descent. After the application of stringent quality thresholds, data from 4,506 markers in 2,692 individuals were included in the analysis. Multipoint nonparametric linkage analysis revealed highly significant linkage in the major histocompatibility complex (MHC) on chromosome 6p21 (maximum LOD score [MLS] 11.66) and suggestive linkage on chromosomes 17q23 (MLS 2.45) and 5q33 (MLS 2.18). This set of markers achieved a mean information extraction of 79.3% across the genome, with a Mendelian inconsistency rate of only 0.002%. Stratification based on carriage of the multiple sclerosis–associated DRB1*1501 allele failed to identify any other region of linkage with genomewide significance. However, ordered-subset analysis suggested that there may be an additional locus on chromosome 19p13 that acts independent of the main MHC locus. These data illustrate the substantial increase in power that can be achieved with use of the latest tools emerging from the Human Genome Project and indicate that future attempts to systematically identify susceptibility genes for multiple sclerosis will have to involve large sample sizes and an association-based methodology.     

Robust estimation of experimentwise P values applied to a genome scan of multiple asthma traits identifies a new region of significant linkage on chromosome 20q13

Over 30 genomic regions show linkage to asthma traits. Six asthma genes have been cloned, but the putative loci in many linked regions have not been identified. To search for asthma susceptibility loci, we performed genomewide univariate linkage analyses of seven asthma traits, using 202 Australian families ascertained through a twin proband. House-dust mite sensitivity (Dpter) exceeded the empirical threshold for significant linkage at 102 cM on chromosome 20q13, near marker D20S173 (empirical pointwise P = .00001 and genomewide P = .005, both uncorrected for multiple-trait testing). Atopy, bronchial hyperresponsiveness (BHR), and forced expiratory volume in 1 s (FEV1) were also linked to this region. In addition, 16 regions were linked to at least one trait at the suggestive level, including 12q24, which has consistently shown linkage to asthma traits in other studies. Some regions were expected to be false-positives arising from multiple-trait testing. To address this, we developed a new approach to estimate genomewide significance that accounts for multiple-trait testing and for correlation between traits and that does not require a Bonferroni correction. With this approach, Dpter remained significantly linked to 20q13 (empirical genomewide P = .042), and airway obstruction remained linked to 12q24 at the suggestive level. Finally, we extended this method to show that the linkage of Dpter, atopy, BHR, FEV1, asthma, and airway obstruction to chromosome 20q13 is unlikely to be due to chance and may result from a quantitative trait locus in this region that affects several of these traits.     

A genomewide search finds major susceptibility loci for nicotine dependence on chromosome 10 in African Americans

Epidemiological studies have demonstrated that genetic factors account for at least 50% of the liability for nicotine dependence (ND). Although several linkage studies have been conducted, all samples to date were primarily of European origin. In this study, we conducted a genomewide scan of 1,261 individuals, representing 402 nuclear families, of African American (AA) origin. We examined 385 autosomal microsatellite markers for ND, which was assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerstrom Test for ND (FTND). After performing linkage analyses using various methods implemented in the GENEHUNTER and S.A.G.E. programs, we found a region near marker D10S1432 on chromosome 10q22 that showed a significant linkage to indexed SQ, with a maximum LOD score of 4.17 at 92 cM and suggestive linkage to HSI, SQ, and log-transformed SQ. Additionally, we identified three regions that met the criteria for suggestive linkage to at least one ND measure: on chromosomes 9q31 at marker D9S1825, 11p11 between markers D11S1993 and D11S1344, and 13q13 between markers D13S325 and D13S788. Other locations on chromosomes 15p11, 17q25, and 18q12 exhibited some evidence of linkage for ND (LOD >1.44). The four regions with significant or suggestive linkage were positive for multiple ND measures by multiple statistical methods. Some of these regions have been linked to smoking behavior at nominally significant levels in other studies, which provides independent replication of the regions for ND in different cohorts. In summary, we found significant linkage on chromosome 10q22 and suggestive linkage on chromosomes 9, 11, and 13 for major genetic determinants of ND in an AA sample. Further analysis of these positive regions by fine mapping and/or association analysis is thus warranted. To our knowledge, this study represents the first genomewide linkage scan of ND in an AA sample.