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J D Terwilliger

Publications and source records attributed to J D Terwilliger.

At least 37 records · Page 2Linked to original sources
PubMed2000

Linkage analysis in the presence of errors II: marker-locus genotyping errors modeled with hypercomplex recombination fractions.

It is well known that genotyping errors lead to loss of power in gene-mapping studies and underestimation of the strength of correlations between trait- and marker-locus genotypes. In two-point linkage analysis, these errors can be absorbed in an inflated recombination-fraction estimate, leaving the test statistic quite robust. In multipoint analysis, however, genotyping errors can easily result in false exclusion of the true location of a disease-predisposing gene. In a companion article, we described a "complex-valued" extension of the recombination fraction to accommodate errors in the assignment of trait-locus genotypes, leading to a multipoint LOD score with the same robustness to errors in trait-locus genotypes that is seen with the conventional two-point LOD score. Here, a further extension of this model to "hypercomplex-valued" recombination fractions (hereafter referred to as "hypercomplex recombination fractions") is presented, to handle random and systematic sources of marker-locus genotyping errors. This leads to a multipoint method (either "model-based" or "model-free") with the same robustness to marker-locus genotyping errors that is seen with conventional two-point analysis but with the advantage that multiple marker loci can be used jointly to increase meiotic informativeness. The cost of this increased robustness is a decrease in fine-scale resolution of the estimated map location of the trait locus, in comparison with traditional multipoint analysis. This probability model further leads to algorithms for the estimation of the lower bounds for the error rates for genomewide and locus-specific genotyping, based on the null-hypothesis distribution of the LOD-score statistic in the presence of such errors. It is argued that those genome scans in which the LOD score is 0 for >50% of the genome are likely to be characterized by high rates of genotyping errors in general.

Algorithms↗
PubMed2000

Genome-wide scan of predisposing loci for increased diastolic blood pressure in Finnish siblings.

OBJECTIVES: To review, on a genome-wide scale, a linkage result obtained in an earlier candidate gene analysis in this same study sample, and to look for other possible contributing genetic loci predisposing to hypertension in this population. DESIGN: An affected sibpair linkage study with highly polymorphic genetic markers spanning the genome at an average intermarker density of 10 cM. PARTICIPANTS: A total of 47 families with two affected siblings (mostly dizygotic twins) and all available additional family members from the genetic isolate of Finland. The families were identified through the Finnish Twin Cohort Study, the total number of this follow-up cohort being 13,888. The study sample was selected on the basis of early-onset hypertension with minimal presence of other phenotypic risk factors such as obesity. RESULTS: The AT1 locus stood out as the most significant locus in this population (maximum likelihood score 4.04). Some evidence for linkage was also detected with markers on chromosomes 2q (maximum likelihood score 2.96), 22q (2.07), and Xp (2.41). CONCLUSIONS: Our results establish the role of the AT1 locus, on a genome-wide scale, as a major contributing locus to essential hypertension in this study sample.

Blood Pressure↗
PubMed2000

Gene mapping in the 20th and 21st centuries: statistical methods, data analysis, and experimental design.

In the 20th century geneticists began to unravel some of the simpler aspects of the etiology of inherited diseases in humans. The theory of linkage analysis was developed and applied long before the advent of molecular biology, but only the technological advances of the second half of the 20th century made large-scale gene mapping with a dense genome-spanning set of markers a reality. More recently, the primary topic of interest has shifted from simple Mendelian diseases, for which genotypes of some gene are the cause of disease, to more complex diseases, for which genotypes of some set of genes together with environmental factors merely alter the probability that an individual gets the disease, although individual factors are typically insufficient to cause the disease outright. To this end, a great deal of dogma has evolved about the best way to skin this cat, although to date success has been minimal with any approach. We postulate that the main reason for this is a lack of attention to experimental design. Once the data have been ascertained, the most powerful statistical methods will not be able to salvage an inappropriately designed study (Andersen 1990). Each phenotype and/or population mandates its own individually tailored study design to maximize the chances of successful gene mapping. We suggest that careful consideration of the available data from real genotype-phenotype correlation studies (as opposed to oversimplified theoretically tractable models), and the practical feasibility of different ascertainment schemes dictate how one should proceed. In this review we review the theory and practice of gene mapping at the close of the 20th century, showing that most methods of linkage and linkage disequilibrium analysis are similar in a fundamental sense, with the differences being related more to study design and ascertainment than to technical details of the underlying statistical analysis. To this end, we propose a new focus in the field of statistical genetics that more explicitly highlights the primacy of study design as the means to increase power for gene mapping.

Algorithms↗
PubMed1999

Gene for hereditary motor and sensory neuropathy (proximal dominant form) mapped to 3q13.1.

Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) has been reported as a new type of HMSN with the disease gene locus in the 3p14.1-q13 region. To further narrow down the gene locus, we performed fine linkage mapping using the linkage disequilibrium method. Analysis of DNA marker haplotypes and genetic cross-over sites showed the disease gene locus to be in the 3.1 cM interval bracketed by D3S1591 and D3S1281. Linkage disequilibrium analysis with DISMULT using 9 marker loci jointly in this region showed a lod score of 4.93 (P < 0.00000095). Consequently, the HMSN-P gene almost certainly lies on chromosome 3q13.1 and shows evidence of linkage disequilibrium.

Chromosome Mapping↗
PubMed1999

A comprehensive linkage analysis of chromosome 21q22 supports prior evidence for a putative bipolar affective disorder locus.

Previously, we demonstrated evidence of linkage to bipolar affective disorder (BP) in a single large, multigenerational family with a LOD score of 3.41 at the PFKL locus on chromosome 21q22.3. Additional families showed little support for linkage to PFKL under homogeneity or heterogeneity, in that study. We have expanded on that analysis, with 31 microsatellite markers at an average marker spacing of </=2 cM, in the largest multigenerational BP pedigree series reported to date. A two-point heterogeneity (alpha=0.5) LOD score of 3.35 (P<.000156) was found at the D21S1260 locus, 5 cM proximal to PFKL. Polylocus analysis with a cluster of three neighboring markers was consistent with these results (PL-HetLOD = 3.25). In the design of this study, 373 individuals from 40 families (from a total set of 1,508 individuals in 57 families) were chosen, as a cost-effective approach to genotyping this large sample set. Linkage analyses were performed with an "affecteds-only" method. As such, our results are based solely on genetic information from affected individuals, without assumptions about the disease-locus genotypes of the unaffecteds. Furthermore, for ease of comparison, this study was performed with the same approach as a 10-cM genome scan for BP loci, the results of which will be reported elsewhere.

Bipolar Disorder↗
PubMed1999

Genomewide scan for familial combined hyperlipidemia genes in finnish families, suggesting multiple susceptibility loci influencing triglyceride, cholesterol, and apolipoprotein B levels.

Familial combined hyperlipidemia (FCHL) is a common dyslipidemia predisposing to premature coronary heart disease (CHD). The disease is characterized by increased levels of serum total cholesterol (TC), triglycerides (TGs), or both. We recently localized the first locus for FCHL, on chromosome 1q21-q23. In the present study, a genomewide screen for additional FCHL loci was performed. In stage 1, we genotyped 368 polymorphic markers in 35 carefully characterized Finnish FCHL families. We identified six chromosomal regions with markers showing LOD score (Z) values >1.0, by using a dominant mode of inheritance for the FCHL trait. In addition, two more regions emerged showing Z>2.0 with a TG trait. In stage 2, we genotyped 26 more markers and seven additional FCHL families for these interesting regions. Two chromosomal regions revealed Z>2.0 in the linkage analysis: 10p11.2, Z=3.20 (theta=.00), with the TG trait; and 21q21, Z=2.24 (theta=.10), with the apoB trait. Furthermore, two more chromosomal regions produced Z>2.0 in the affected-sib-pair analysis: 10q11.2-10qter produced Z=2.59 with the TC trait and Z=2.29 with FCHL, and 2q31 produced Z=2.25 with the TG trait. Our results suggest additional putative loci influencing FCHL in Finnish families, some potentially affecting TG levels and some potentially affecting TC or apoB levels.

Adult↗
PubMed1999

A genomewide screen for schizophrenia genes in an isolated Finnish subpopulation, suggesting multiple susceptibility loci.

Schizophrenia is a severe mental disorder affecting approximately 1% of the world's population. Here, we report the results from a three-stage genomewide screen performed in a study sample from an internal isolate of Finland. An effort was made to identify genes predisposing for schizophrenia that are potentially enriched in this isolate, which has an exceptionally high lifetime risk for this trait. Ancestors of the local families with schizophrenia were traced back to the foundation of the population in the 17th century. This genealogical information was used as the basis for the study strategy, which involved screening for alleles shared among affected individuals originating from common ancestors. We found four chromosomal regions with markers revealing pairwise LOD scores>1.0: 1q32.2-q41 (Z(max)=3.82, dominant affecteds-only model), 4q31 (Z(max)=2. 74, dominant 90%-penetrance model), 9q21 (Z(max)=1.95, dominant 90%-penetrance model), and Xp11.4-p11.3 (Z(max)=2.01, recessive 90%-penetrance model). This finding suggests that there are several putative loci predisposing to schizophrenia, even in this isolate.

Adult↗
PubMed1999

Genome scan for predisposing loci for distal interphalangeal joint osteoarthritis: evidence for a locus on 2q.

The genetic contribution to common forms of osteoarthritis (OA) is well established but poorly understood. We performed a genome scan, using 302 markers for loci predisposing to distal interphalangeal joint (DIP) OA. To minimize genetic heterogeneity in our study sample, we identified siblings with a severe, radiologically defined phenotype from the nationwide registers of Finland. In the initial genome scan, linkage analysis in 27 sibships gave a pairwise LOD score (Z) >1.00 with nine of the screening markers. In the second stage, additional markers and family members were genotyped in these chromosomal regions. On 2q12-q13, IL1R1 resulted in Z=2.34 at recombination fraction (theta) 0, allowing a dominant mode of inheritance. Association analysis of markers D2S2264, IL1R1, D2S373, and D2S1789 jointly provided some evidence for a shared haplotype among the affected individuals (P value of.012). Also, multipoint nonparametric linkage analysis yielded a P value of.0001 near the locus IL1R1 and P=.0007 approximately 20 cM telomeric near marker D2S1399, which, in two-point analysis, gave Z=1.48 (straight theta=. 02). This chromosomal region on 2q harbors the interleukin 1 gene cluster and, thus, represents a good candidate region for inflammatory and autoimmune disorders. Three additional chromosomal regions-4q26-q27, 7p15-p21, and Xcen-also provided some evidence for linkage, and further analyses would be justified to clarify their potential involvement in the genetic predisposition to DIP OA.

Adult↗
PubMed1998

Linkage disequilibrium mapping of complex disease: fantasy or reality?

In the past year, data about the level and nature of linkage disequilibrium between alleles of tightly linked SNPs have started to become available. Furthermore, increasing evidence of allelic heterogeneity at the loci predisposing to complex disease has been observed, which has lead to initial attempts to develop methods of linkage disequilibrium detection allowing for this difficulty. It has also become more obvious that we will need to think carefully about the types of populations we need to analyze in an attempt to identify these elusive genes, and it is becoming clear that we need to carefully re-evaluate the prognosis of the current paradigm with regard to its robustness to the types of problems that are likely to exist.

Chromosome Mapping↗
PubMed1998

Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23.

More than half of the patients with angiographically confirmed premature coronary heart disease (CHD) have a familial lipoprotein disorder. Familial combined hyperlipidaemia (FCHL) represents the most common genetic dyslipidemia with a prevalence of 1.0-2.0%. FCHL is estimated to cause 10-20% of premature CHD and is characterized by elevated levels of cholesterol, triglycerides, or both. Attempts to characterize genes predisposing to FCHL have been hampered by its equivocal phenotype definition, unknown mode of inheritance and genetic heterogeneity. In order to minimize genetic heterogeneity, we chose 31 extended FCHL families from the isolated Finnish population that fulfilled strictly defined criteria for the phenotype status. We performed linkage analyses with markers from ten chromosomal regions that contain lipid-metabolism candidate genes. One marker, D1S104, adjacent to the apolipoprotein A-II (APOA2) gene on chromosome 1, revealed a lod score of Z = 3.50 assuming a dominant mode of inheritance. Multipoint analysis combining information from D1S104 and the neighbouring marker D1S1677 resulted in a lod score of 5.93. Physical positioning of known genes in the area (APOA2 and three selectin genes) outside the linked region suggests a novel locus for FCHL on 1q21-q23. A second paper in this issue (Castellani et al.) reports the identification of a mouse combined hyperlipidaemia locus in the syntenic region of the mouse genome, thus further implicating a gene in this region in the aetiology of FCHL.

Adult↗
PubMed1998

Linkage analysis of putative schizophrenia gene candidate regions on chromosomes 3p, 5q, 6p, 8p, 20p and 22q in a population-based sampled Finnish family set.

During the past decade numerous studies have been published describing chromosomal regions potentially linked with schizophrenia. Unfortunately, none of these studies has been able to conclusively identify any specific gene that predisposes to schizophrenia. Typically evidence for linkage is seen on large chromosomal regions, as expected, containing tens or even hundreds of genes. Furthermore, attempts to replicate the findings have rarely been successful leaving a confusion about the existence of predisposing genes for schizophrenia in a particular region of the genome. We have carried out linkage analysis in a set of 62 pedigrees rising from a genetically isolated population of Finland with markers on six chromosomal regions earlier suggested to harbor predisposing genes for schizophrenia, namely 3p, 5q, 6p, 8p, 20p, and 22q. We were not able to find significant evidence for linkage on any of these chromosomal regions. However, some support for linkage was found on all studied chromosomal regions, except 3p.

Case-Control Studies↗
PubMed1998

Assignment of the locus for PLO-SL, a frontal-lobe dementia with bone cysts, to 19q13.

PLO-SL (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy) is a recessively inherited disorder characterized by systemic bone cysts and progressive presenile frontal-lobe dementia, resulting in death at <50 years of age. Since the 1960s, approximately 160 cases have been reported, mainly in Japan and Finland. The pathogenesis of the disease is unknown. In this article, we report the assignment of the locus for PLO-SL, by random genome screening using a modification of the haplotype-sharing method, in patients from a genetically isolated population. By screening five patient samples from 2 Finnish families, followed by linkage analysis of 12 Finnish families, 3 Swedish families, and 1 Norwegian family, we were able to assign the PLO-SL locus to a 9-cM interval between markers D19S191 and D19S420 on chromosome 19q13. The critical region was further restricted, to approximately 1.8 Mb, by linkage-disequilibrium analysis of the Finnish families. According to the haplotype analysis, one Swedish and one Norwegian PLO-SL family are not linked to the chromosome 19 locus, suggesting that PLO-SL is a heterogeneous disease. In this chromosomal region, one potential candidate gene for PLO-SL, the gene encoding amyloid precursor-like protein 1, was analyzed, but no mutations were detected in the coding region.

Adolescent↗
PubMed1998

Concordance for sex and the pseudoautosomal gene hypothesis revisited: no evidence of increased sex concordance in a nationwide Finnish sample of siblings with paternally derived schizophrenia.

OBJECTIVE: This study set out to determine, in a homogeneous sample with nationwide coverage in Finland, whether siblings treated for schizophrenia are more often of the same sex than expected by chance, and whether this is especially so when the disorder is transmitted by their fathers. METHOD: Finnish social and health insurance files as well as hospital discharge registers were searched for probands with schizophrenia from a birth cohort spanning 30 years. Nuclear families were identified by cross-linkage with the national birth register, and the sex distribution observed in multiply affected sibships was compared with expected distributions by maximum likelihood analysis. RESULTS: In the subset of multiply affected sibships with one parent who had schizophrenia (84 fathers and 120 mothers), the observed sex distribution did not deviate from the expected pattern. However, a small and marginally significant excess of sex concordance emerged from the total sample of 1,942 sibships in which there were at least two affected members, irrespective of the parents' affection status. CONCLUSIONS: The results indicate that no above-chance sex concordance in sibships multiply affected with paternally transmitted schizophrenia is present in the genetically homogeneous population of Finland. In view of a virtually unbiased and complete ascertainment procedure and sample sizes one to two orders of magnitude larger than those in previous studies, the authors attribute prior findings of such a concordance to sampling artifacts or chance fluctuations and finally conclude that except for regional genetic isolates, there is no epidemiologic evidence that a gene accounting for substantial susceptibility to schizophrenia in a greater proportion of cases resides in the pseudoautosomal region of the sex chromosomes.

Cohort Studies↗
PubMed1997

Schizophrenia in the genetic isolate of Finland.

We compared the features of schizophrenia in the homogeneous population of Finland (population about 5,000,000) and in an internal isolate in northeastern Finland inhabited in the 1680s by a small group of founders (current population about 18,000) in a register-based epidemiological study. We identified all cases with a diagnosis of schizophrenia in Finland born between 1940-1969 using three national computerized registers and found a total of 267 schizophrenia patients in the internal isolate and 29,124 in Finland. The lifetime prevalence was 2.21% in the internal isolate and 1.21% in Finland, respectively. The age-corrected lifetime risk was 3.2% in the internal isolate and 1.1% in the whole country. The risk of schizophrenia to siblings in the internal isolate was 6.4% (95% confidence interval 0.052, 0.078), 9.1% (95% CI 0.062, 0.130), and 6.8% (95% CI 0.028, 0.135) given 1, 2, or 3 affected siblings, and for all Finland 4.2% (95% CI 0.036, 0.043), 6.4% (95% CI 0.058, 0.071), and 8.7% (95% CI 0.068, 0.107) given 1, 2, or 3, affected siblings, respectively. The mean number of children in schizophrenia families and thus the number of families having at least two affected individuals were clearly higher in the isolate (24.9% vs 9.2%). We did not find any other epidemiological features differing between these two regions. It seems that the family material collected from the internal isolate is a representative subsample from the entire country and hopefully it enables easier identification of at least some predisposing genes for schizophrenia due to its unique population structure.

Adult↗
PubMed1997

Genomewide scan of multiple sclerosis in Finnish multiplex families.

Multiple sclerosis (MS) is a neurological, demyelinating disorder with a putative autoimmune etiology. It is thought to be a multifactorial disease with a complex mode of inheritance. Here we report the results of a two-stage genomewide scan for loci predisposing to MS. The first stage of the screen, with a low-resolution map, was performed in a selection of 16 pedigrees collected from an isolated Finnish population. Multipoint, non-parametric linkage analysis of the 328 markers did not reveal statistically significant results. However, 10 slightly interesting regions (P = .1-.15) emerged, including our previous findings of the HLA complex on 6p21 and a putative locus on 5p14-p12. Eight of these novel regions were further analyzed by use of denser marker maps, in the second stage of the scan. For the chromosomal regions 4cen, 11tel, and 17q, the statistical significance increased, but not conclusively; for 2q32 and 10q21, the statistical significance did not change. Accordingly, genotyping of the high-density markers in these regions was performed, and the data were analyzed by use of two-point, parametric linkage analysis using the complete pedigree information of the 21 Finnish multiplex families. We detected suggestive evidence for a predisposing locus on chromosomal region 17q22-q24. Several markers on 17q22-q24 yielded positive LOD scores, with the maximum LOD score (Zmax) occurring with D17S807 (Zmax = 2.8, theta = .04; dominant model). Interestingly, a suggestive linkage between MS and the markers on 17q22-q24 was also revealed by a recent genomewide scan in MS families from the United Kingdom.

Autoimmune Diseases↗
PubMed1997

True and false positive peaks in genomewide scans: applications of length-biased sampling to linkage mapping.

Disease-susceptibility loci are now being mapped via genomewide scans in which a linkage statistic is computed at each of a large number of markers. Such disease-susceptibility loci may be identified via a peak in the test statistic when the latter is plotted against the genetic map. In this paper we establish, by appealing to renewal theory, that true positive peaks are expected to be longer than false positive peaks. These results are verified by a realistic simulation of a genomewide linkage study based on the affected-sib-pair design. Since longer peaks are more likely to contain a gene of interest than are shorter peaks, these differences may aid in linkage mapping, justifying assignment of lower priority to shorter peaks. However, since these differences are generally small, statistics based on both peak length and height may not be much more powerful than those based on height alone. The results presented here also provide a theoretical framework for methods that use the length of shared haplotypes in populations to map disease genes.

Chromosome Mapping↗