Linkage of Bipolar Affective Disorder to Chromosome 18 Markers in a New Pedigree Series

Several groups have reported evidence suggesting linkage of bipolar affective disorder (BPAD) to chromosome 18. We have reported data from 28 pedigrees that showed linkage to marker loci on 18p and to loci 40 cM distant on 18q. Most of the linkage evidence derived from families with affected phenotypes in only the paternal lineage and from marker alleles transmitted on the paternal chromosome. We now report results from a series of 30 new pedigrees (259 individuals) genotyped for 13 polymorphic markers spanning chromosome 18. Subjects were interviewed by a psychiatrist and were diagnosed by highly reliable methods. Genotypes were generated with automated technology and were scored blind to phenotype. Affected sib pairs showed excess allele sharing at the 18q markers D18S541 and D18S38. A parent-of-origin effect was observed, but it was not consistently paternal. No robust evidence of linkage was detected for markers elsewhere on chromosome 18. Multipoint nonparametric linkage analysis in the new sample combined with the original sample of families supports linkage on chromosome 18q, but the susceptibility gene is not well localized.     

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.     

Association studies of QTL for multi-allele markers by mixed models

In this paper, we extend association study methods of both Fan et al. [Hum Hered 2002;53:130-145], in which a quantitative trait locus (QTL) and a multi-allele marker are considered for trio families, and Fan and Xiong [Biostatistics 2003, in press], in which a QTL and a bi-allelic marker are considered for nuclear families. The objective is to build mixed models for association study between a QTL and a multi-allelic marker for nuclear families with any number of offspring. Two types of nuclear family data are considered: the first is genetic data of offspring from at least one heterozygous parents, and the second is genetic data of offspring of nuclear family. (1) For the data of offspring from at least one heterozygous parents, we assume that at least one parent is heterozygous at the marker locus, and we may infer clearly the transmission of parental marker alleles to the offspring. We show that it can be used in association study in the presence of linkage. The theoretical basis is the difference between the conditional mean of trait value given an allele is transmitted and the conditional mean of trait value given the allele is not transmitted from a heterozygous parent. To build valid models, we calculate the variance covariance structure of trait values of offspring. Besides, the reduction of the number of parameters is discussed under an assumption of tight linkage between the trait locus and the marker. (2) For the data of offspring of nuclear family, we show that it can be used in general association study. In this case, the theoretical basis is the difference between the conditional mean of trait values given an allele is transmitted from a parent and the population mean. Then, we calculate variance-covariance structure of trait values of offspring. (3) Based on the theoretical analysis, mixed models are built for each type of the data, and related test statistics are proposed for association study. By power calculation and comparison, we show that, in some instances, the proposed test statistics have higher power than that by collapsing alleles to be new ones. The proposed models are used to analyze chromosomes 4 and chromosome 16 data of the Oxford asthma data, Genetic Analysis Workshop 12.     

Evidence for asthma susceptibility genes on chromosome 11 in an African-American population

Initial genome-wide scan data provided suggestive evidence for linkage of the asthma phenotype in African-American (AA), but not Caucasian, families to chromosome 11q markers (peak at D11S1985; LOD=2). To refine this region, mapping analysis of 91 AA families (51 multiplex families and 40 asthmatic case-parent trios) was performed with an additional 17 markers flanking the initial peak linkage marker. Multipoint analyses of the 51 multiplex families yielded significant evidence of linkage with a peak non-parametric linkage score of 4.38 at marker D11S1337 (map position 68.6 cM). Furthermore, family-based association and transmission disequilibrium tests conducted on all 91 families showed significant evidence of linkage in the presence of disequilibrium for several individual markers in this region. A putative susceptibility locus was estimated to be at map position 70.8 cM with a confidence interval spanning the linkage peak. Evidence from both linkage and association analyses suggest that this region of chromosome 11 contains one or more susceptibility genes for asthma in these AA families.     

Evidence for a prostate cancer linkage to chromosome 20 in 159 hereditary prostate cancer families

Prostate cancer is the most common malignancy diagnosed in men in the US. Genetic susceptibility to prostate cancer has been well documented. A region at chromosome 20q13 (HPC20) has been reported to be linked to a prostate cancer susceptibility gene. To confirm this finding, we genotyped 16 markers spanning approximately 95 cM on chromosome 20 in 159 hereditary prostate cancer (HPC) families. Positive (but not statistically significant) linkage scores were observed from 20pter to 20q11, with the highest non-parametric linkage (NPL) score for the complete dataset of 1.02 (P=0.15) being observed at D20S195 at 20q11. Evidence for linkage from parametric analyses with a dominant or a recessive model was weak. Interestingly, consistent with the original findings of linkage to 20 g higher linkage scores were observed in the subsets of families with a later age at diagnosis (> or =65 years; n=80, NPL=1.94, P=0.029 at D20S186), fewer than five affected family members (n=69, NPL=1.74, P=0.037 at D20S889), or without male-to-male disease transmission (n=60, NPL=1.01, P=0.15 at D20S117). The region with positive linkage scores spanned approximately 60 cM from 20pter to 20q11 in these subsets of families. Our results are consistent with a prostate cancer susceptibility locus on chromosome 20.     

A susceptibility locus for migraine with aura, on chromosome 4q24

Migraine is a complex neurovascular disorder with substantial evidence supporting a genetic contribution. Prior attempts to localize susceptibility loci for common forms of migraine have not produced conclusive evidence of linkage or association. To date, no genomewide screen for migraine has been published. We report results from a genomewide screen of 50 multigenerational, clinically well-defined Finnish families showing intergenerational transmission of migraine with aura (MA). The families were screened using 350 polymorphic microsatellite markers, with an average intermarker distance of 11 cM. Significant evidence of linkage was found between the MA phenotype and marker D4S1647 on 4q24. Using parametric two-point linkage analysis and assuming a dominant mode of inheritance, we found for this marker a maximum LOD score of 4.20 under locus homogeneity (P=.000006) or locus heterogeneity (P=.000011). Multipoint parametric (HLOD = 4.45; P=.0000058) and nonparametric (NPL(all) = 3.43; P=.0007) analyses support linkage in this region. Statistically significant linkage was not observed in any other chromosomal region.     

Autosomal dominant nonsyndromic cleft lip and palate: significant evidence of linkage at 18q21.1

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common congenital facial defects, with an incidence of 1 in 700-1,000 live births among individuals of European descent. Several linkage and association studies of NSCL/P have suggested numerous candidate genes and genomic regions. A genomewide linkage analysis of a large multigenerational family (UR410) with NSCL/P was performed using a single-nucleotide-polymorphism array. Nonparametric linkage (NPL) analysis provided significant evidence of linkage for marker rs728683 on chromosome 18q21.1 (NPL=43.33 and P=.000061; nonparametric LOD=3.97 and P=.00001). Parametric linkage analysis with a dominant mode of inheritance and reduced penetrance resulted in a maximum LOD score of 3.61 at position 47.4 Mb on chromosome 18q21.1. Haplotype analysis with informative crossovers defined a 5.7-Mb genomic region spanned by proximal marker rs1824683 (42,403,918 bp) and distal marker rs768206 (48,132,862 bp). Thus, a novel genomic region on 18q21.1 was identified that most likely harbors a high-risk variant for NSCL/P in this family; we propose to name this locus "OFC11" (orofacial cleft 11).     

X-APL: an improved family-based test of association in the presence of linkage for the X chromosome

Family-based association methods have been developed primarily for autosomal markers. The X-linked sibling transmission/disequilibrium test (XS-TDT) and the reconstruction-combined TDT for X-chromosome markers (XRC-TDT) are the first association-based methods for testing markers on the X chromosome in family data sets. These are valid tests of association in family triads or discordant sib pairs but are not theoretically valid in multiplex families when linkage is present. Recently, XPDT and XMCPDT, modified versions of the pedigree disequilibrium test (PDT), were proposed. Like the PDT, XPDT compares genotype transmissions from parents to affected offspring or genotypes of discordant siblings; however, the XPDT can have low power if there are many missing parental genotypes. XMCPDT uses a Monte Carlo sampling approach to infer missing parental genotypes on the basis of true or estimated population allele frequencies. Although the XMCPDT was shown to be more powerful than the XPDT, variability in the statistic due to the use of an estimate of allele frequency is not properly accounted for. Here, we present a novel family-based test of association, X-APL, a modification of the test for association in the presence of linkage (APL) test. Like the APL, X-APL can use singleton or multiplex families and properly infers missing parental genotypes in linkage regions by considering identity-by-descent parameters for affected siblings. Sampling variability of parameter estimates is accounted for through a bootstrap procedure. X-APL can test individual marker loci or X-chromosome haplotypes. To allow for different penetrances in males and females, separate sex-specific tests are provided. Using simulated data, we demonstrated validity and showed that the X-APL is more powerful than alternative tests. To show its utility and to discuss interpretation in real-data analysis, we also applied the X-APL to candidate-gene data in a sample of families with Parkinson disease.     

Genomewide linkage scan identifies a novel susceptibility locus for restless legs syndrome on chromosome 9p

Restless legs syndrome (RLS) is a common neurological disorder that affects 5%-12% of all whites. To genetically dissect this complex disease, we characterized 15 large and extended multiplex pedigrees, consisting of 453 subjects (134 affected with RLS). A familial aggregation analysis was performed, and SAGE FCOR was used to quantify the total genetic contribution in these families. A weighted average correlation of 0.17 between first-degree relatives was obtained, and heritability was estimated to be 0.60 for all types of relative pairs, indicating that RLS is a highly heritable trait in this ascertained cohort. A genomewide linkage scan, which involved >400 10-cM-spaced markers and spanned the entire human genome, was then performed for 144 individuals in the cohort. Model-free linkage analysis identified one novel significant RLS-susceptibility locus on chromosome 9p24-22 with a multipoint nonparametric linkage (NPL) score of 3.22. Suggestive evidence of linkage was found on chromosome 3q26.31 (NPL score 2.03), chromosome 4q31.21 (NPL score 2.28), chromosome 5p13.3 (NPL score 2.68), and chromosome 6p22.3 (NPL score 2.06). Model-based linkage analysis, with the assumption of an autosomal-dominant mode of inheritance, validated the 9p24-22 linkage to RLS in two families (two-point LOD score of 3.77; multipoint LOD score of 3.91). Further fine mapping confirmed the linkage result and defined this novel RLS disease locus to a critical interval. This study establishes RLS as a highly heritable trait, identifies a novel genetic locus for RLS, and will facilitate further cloning and identification of the genes for RLS.     

Genomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22

Previous linkage studies in schizophrenia have been discouraging due to inconsistent findings and weak signals. Genetic heterogeneity has been cited as one of the primary culprits for such inconsistencies. We have performed a 10-cM autosomal genomewide linkage scan for schizophrenia susceptibility regions, using 29 multiplex families of Ashkenazi Jewish descent. Although there is no evidence that the rate of schizophrenia among the Ashkenazim differs from that in other populations, we have focused on this population in hopes of reducing genetic heterogeneity among families and increasing the detectable effects of any particular locus. We pursued both allele-sharing and parametric linkage analyses as implemented in Genehunter, version 2.0. Our strongest signal was achieved at chromosome 10q22.3 (D10S1686), with a nonparametric linkage score (NPL) of 3.35 (genomewide empirical P=.035) and a dominant heterogeneity LOD score (HLOD) of 3.14. Six other regions gave NPL scores >2.00 (on chromosomes 1p32.2, 4q34.3, 6p21.31, 7p15.2, 15q11.2, and 21q21.2). Upon follow-up with an additional 23 markers in the chromosome 10q region, our peak NPL score increased to 4.27 (D10S1774; empirical P=.00002), with a 95% confidence interval of 12.2 Mb for the location of the trait locus (D10S1677 to D10S1753). We find these results encouraging for the study of schizophrenia among Ashkenazi families and suggest further linkage and association studies in this chromosome 10q region.     

Models and tests of linkage and association studies of quantitative trait locus for multi-allele marker Loci

In this paper, we explore models and tests for association and linkage studies of a quantitative trait locus (QTL) linked to a multi-allele marker locus. Based on the difference between an offspring's conditional trait means of receiving and not receiving an allele from a parent at marker locus, we propose three statistics T(m), T(m,row) and T(m,col) to test association or linkage disequilibrium between the marker locus and the QTL. These tests are composite tests, and use the offspring marginal sample means including offspring data of both homozygous and heterozygous parents. For the linkage study, we calculate the offspring's conditional trait mean given the allele transmission status of a heterozygous parent at the marker locus. Based on the difference between the conditional means of a transmitted and a nontransmitted allele from a heterozygous parent, we propose statistics T(parsi), T(satur), T(gen) and T(m,het) to perform composite tests of linkage between the marker locus and the quantitative trait locus in the presence of association. These tests only use the offspring data that are related to the heterozygous parents at the marker locus. T(parsi) is a parsimonious or allele-wise statistic, T(satur) and T(gen )are satured or genotype-wise statistics, and T(m,het) compares the row and column sample means for offspring data of heterozygous parents. After comparing the powers and the sample sizes, we conclude that T(parsi) has higher power than those of the bi-allele tests, T(satur), T(gen), and T(m,het). If there is tight linkage between the marker and the trait locus, T(parsi) is powerful in detecting linkage between the marker and the trait locus in the presence of association. By investigating the goodness-of-fit of T(parsi), we find that T(satur) does not gain much power compared to that of T(parsi). Moreover, T(parsi) takes into account the pattern of the data that is consistent with linkage and linkage disequilibrium. As the number of alleles at the marker locus increases, T(parsi) is very conservative, and can be useful even for sparse data. To illustrate the usefulness and the power of the methods proposed in this paper, we analyze the chromosome 6 data of the Oxford asthma data, Genetic Analysis Workshop 12.     

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.     

Evidence for a new Graves disease susceptibility locus at chromosome 18q21

Graves disease (GD) is a common autoimmune thyroid disorder that is inherited as a complex multigenic trait. By using a single microsatellite marker at each locus, we screened the type 1 diabetes loci IDDM4, IDDM5, IDDM6, IDDM8, and IDDM10 and the fucosyltransferase-2 locus for linkage in sib pairs with GD. This showed a two-point nonparametric linkage (NPL) score of 1.57 (P=.06) at the IDDM6 marker D18S41, but NPL scores were <1.0 at the other five loci. Thus, the investigation of the IDDM6 locus was extended by genotyping 11 microsatellite markers spanning 48 cM across chromosome 18q12-q22 in 81 sib pairs affected with autoimmune thyroid disease (AITD). Multipoint analysis, designating all AITD sib pairs as affected, showed a peak NPL score of 3.46 (P=.0003), at the marker D18S487. Designation of only GD cases as affected (74 sib pairs) showed a peak NPL score of 3.09 (P=.001). Linkage to this region has been demonstrated in type 1 diabetes (IDDM6), rheumatoid arthritis, and systemic lupus erythematosus, which suggests that this locus may have a role in several forms of autoimmunity.     

Evidence for a prostate cancer-susceptibility locus on chromosome 20

Recent studies suggest that hereditary prostate cancer is a complex disease involving multiple susceptibility genes and variable phenotypic expression. While conducting a genomewide search on 162 North American families with > or =3 members affected with prostate cancer (PRCA), we found evidence for linkage to chromosome 20q13 with two-point parametric LOD scores >1 at multiple sites, with the highest two-point LOD score of 2.69 for marker D20S196. The maximum multipoint NPL score for the entire data set was 3.02 (P=.002) at D20S887. On the basis of findings from previous reports, families were stratified by the presence (n=116) or absence (n=46) of male-to-male transmission, average age of diagnosis (<66 years, n=73; > or =66 years, n=89), and number of affected individuals (<5, n=101; > or =5, n=61) for further analysis. The strongest evidence of linkage was evident with the pedigrees having <5 family members affected with prostate cancer (multipoint NPL 3.22, P=.00079), a later average age of diagnosis (multipoint NPL 3.40, P=.0006), and no male-to-male transmission (multipoint NPL 3.94, P=.00007). The group of patients having all three of these characteristics (n=19) had a multipoint NPL score of 3.69 (P=.0001). These results demonstrate evidence for a PRCA susceptibility locus in a subset of families that is distinct from the groups more likely to be linked to previously identified loci.     

Chromosome-12 Mapping of Late-Onset Alzheimer Disease among Caribbean Hispanics

Linkage to chromosome 12p for familial Alzheimer disease (AD) has been inconsistent. Using 35 markers near the centromere of chromosome 12, we investigated 79 Caribbean Hispanic families with AD. Two-point linkage analysis using affected sib pairs yielded LOD scores of 3.15 at D12S1623 and 1.43 at D12S1042. The LOD score at D12S1623 decreased to 1.62 in families with late-onset (age >65 years) AD (LOAD), but the LOD score at D12S1042 was unchanged. Among families negative for the apolipoprotein E (APOE-epsilon 4) allele, the LOD score for D12S1623 was lower (1.01), whereas that for D12S1042 increased to 1.73. Among families positive for the APOE-epsilon 4 allele, none of the LOD scores reached 1. Multipoint affected-relative-pair analysis showed peaks at D12S1623 (nonparametric linkage [NPL] score 1.52; P=.028) and near D12S1042, at D12S1057 (NPL score 1.57; P=.027). NPL scores for both D12S1623 and D12S1057 increased in families affected with LOAD, but, in APOE-epsilon 4-negative families, only scores for the region flanking D12S1623 remained elevated (NPL score 1.74; P=.013). This study of Caribbean Hispanics with familial AD extends and provides modest evidence of linkage to loci on chromosome 12p. Linkage varied by age at onset of AD and by the presence or absence of the APOE-epsilon 4 allele.     

Evidence for Linkage of Bipolar Disorder to Chromosome 18 with a Parent-of-Origin Effect

A susceptibility gene on chromosome 18 and a parent-of-origin effect have been suggested for bipolar affective disorder (BPAD). We have studied 28 nuclear families selected for apparent unilineal transmission of the BPAD phenotype, by using 31 polymorphic markers spanning chromosome 18. Evidence for linkage was tested with affected-sib-pair and LOD score methods under two definitions of the affected phenotype. The affected-sib-pair analyses indicated excess allele sharing for markers on 18p within the region reported previously. The greatest sharing was at D18S37: 64% in bipolar and recurrent unipolar (RUP) sib pairs (P = .0006). In addition, excess sharing of the paternally, but not maternally, transmitted alleles was observed at three markers on 18q: at D18S41, 51 bipolar and RUP sib pairs were concordant for paternally transmitted alleles, and 21 pairs were discordant (P = .0004). The evidence for linkage to loci on both 18p and 18q was strongest in the 11 paternal pedigrees, i.e., those in which the father or one of the father's sibs is affected. In these pedigrees, the greatest allele sharing (81%; P = .00002) and the highest LOD score (3.51; θ = 0.0) were observed at D18S41. Our results provide further support for linkage of BPAD to chromosome 18 and the first molecular evidence for a parent-of-origin effect operating in this disorder. The number of loci involved, and their precise location, require further study.     

Genomewide Search for Type 2 Diabetes Mellitus Susceptibility Loci in Finnish Families: The Botnia Study

Type 2 diabetes mellitus is a heterogeneous inherited disorder characterized by chronic hyperglycemia resulting from pancreatic beta-cell dysfunction and insulin resistance. Although the pathogenic mechanisms are not fully understood, manifestation of the disease most likely requires interaction between both environmental and genetic factors. In the search for such susceptibility genes, we have performed a genomewide scan in 58 multiplex families (comprising 440 individuals, 229 of whom were affected) from the Botnia region in Finland. Initially, linkage between chromosome 12q24 and impaired insulin secretion had been reported, by Mahtani et al., in a subsample of 26 families. In the present study, we extend the initial genomewide scan to include 32 additional families, update the affectation status, and fine map regions of interest, and we try to replicate the initial stratification analysis. In our analysis of all 58 families, we identified suggestive linkage to one region, chromosome 9p13-q21 (nonparametric linkage [NPL] score 3.9; P<.0002). Regions with nominal P values <.05 include chromosomes 2p11 (NPL score 2.0 [P<.03]), 3p24-p22 (NPL score 2.2 [P<.02]), 4q32-q33 (NPL score 2.5 [P<.01]), 12q24 (NPL score 2.1 [P<.03]), 16p12-11 (NPL score 1.7 [P<.05]), and 17p12-p11 (NPL score 1.9 [P<.03]). When chromosome 12q24 was analyzed in only the 32 additional families, a nominal P value <.04 was observed. Together with data from other published genomewide scans, these findings lend support to the hypothesis that regions on chromosome 9p13-q21 and 12q24 may harbor susceptibility genes for type 2 diabetes.     

Linkage and association analyses of microsatellites and single-nucleotide polymorphisms in nuclear families

Several simulation studies have suggested that a high-density single-nucleotide polymorphisms (SNPs) marker set may be as useful as a traditional microsatellites (MS) marker set in performing whole-genome linkage analysis. However, very few studies have directly tested the SNPs-based genome-wide scan. In the present study, we compared the linkage results from the SNPs-based scan with a map density of 3-cM spacing with those from the MS scan using a 10-cM marker set among 300 nuclear families each from the Aipotu (AI), Danacaa (DA), and Karangar (KA) populations from the simulated Genetic Analysis Workshop 14 Problem 2 data. We found that information contents obtained from the SNPs scan were somewhat lower than those from the MS scan. However, the linkage results obtained from the two scans showed a high degree of similarity. Both scans identified a similar number of chromosomal regions attaining nominal significance (p < 0.05). Specifically, both scans detected confirmed evidence for linkage (NPL >or= 4.07, p = 2 x 10(-5)) to chromosome 1 in the AI families, chromosomes 1 and 3 in the DA families, and chromosomes 3, 5, and 9 in the KA families. An additional confirmed linkage to chromosome 5 in the AI families was detected only by the MS scan. We also observed slightly wider 1-LOD intervals for more of the SNP peaks than for the MS peaks, which is likely due to lower information contents for the SNPs. Subsequent fine-mapping association analysis further identified 2 to 3 markers significantly associated with disease status in each population; B03T3056, B03T3058, and B05T4139 in the AI population, B03T3056 and B03T3058 in the KA population, and B03T3056, B03T3057, and B03T3058 in the DA population. Among the four markers, three were chosen based on results obtained from the two scans, but one was solely from the SNP scan. In summary, our finding suggests that the SNP-based genome scan has the potential to be as powerful as the traditional MS-based scan and offers good identification of peak location for further fine-mapped association analysis.     

DSLINK: a computer program for gene-centromere linkage analysis in families with a trisomic offspring.

Trisomic individuals provide information for gene-centromere mapping, since two of the four chromatids in a meiotic tetrad can be recovered. When centromeric markers are available, linkage analysis between the centromere and any marker locus can be performed in nuclear families having one or more trisomic offspring. Since conventional linkage programs consider only disomic individuals, we have written a FORTRAN computer program, DSLINK, that performs gene-centromere linkage analysis on the basis of information on trisomic and disomic offspring. This program makes it possible to study the relationship between recombination and chromosome segregation.     

Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM).

A population association has consistently been observed between insulin-dependent diabetes mellitus (IDDM) and the "class 1" alleles of the region of tandem-repeat DNA (5'' flanking polymorphism [5''FP]) adjacent to the insulin gene on chromosome 11p. This finding suggests that the insulin gene region contains a gene or genes contributing to IDDM susceptibility. However, several studies that have sought to show linkage with IDDM by testing for cosegregation in affected sib pairs have failed to find evidence for linkage. As means for identifying genes for complex diseases, both the association and the affected-sib-pairs approaches have limitations. It is well known that population association between a disease and a genetic marker can arise as an artifact of population structure, even in the absence of linkage. On the other hand, linkage studies with modest numbers of affected sib pairs may fail to detect linkage, especially if there is linkage heterogeneity. We consider an alternative method to test for linkage with a genetic marker when population association has been found. Using data from families with at least one affected child, we evaluate the transmission of the associated marker allele from a heterozygous parent to an affected offspring. This approach has been used by several investigators, but the statistical properties of the method as a test for linkage have not been investigated. In the present paper we describe the statistical basis for this "transmission test for linkage disequilibrium" (transmission/disequilibrium test [TDT]). We then show the relationship of this test to tests of cosegregation that are based on the proportion of haplotypes or genes identical by descent in affected sibs. The TDT provides strong evidence for linkage between the 5''FP and susceptibility to IDDM. The conclusions from this analysis apply in general to the study of disease associations, where genetic markers are usually closely linked to candidate genes. When a disease is found to be associated with such a marker, the TDT may detect linkage even when haplotype-sharing tests do not.