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PubMed2003

Genetics of chronic obstructive pulmonary disease.

Variability in the susceptibility to develop chronic obstructive pulmonary disease (COPD) is related to both genetic and environmental factors. COPD is likely a genetically complex disease, but severe alpha 1-antitrypsin (AAT) deficiency [e.g., protease inhibitor (PI) Z] remains the only proven genetic risk factor for COPD. Even among PI Z individuals, substantial variability in lung function is observed, suggesting that genetic modifiers may influence the expression of lung disease in severe AAT deficiency. The variable development of COPD in smokers without alpha 1-antitrypsin deficiency and the familial aggregation of lung function measurements also suggest the presence of genetic influences on lung function growth and decline leading to COPD. Many candidate gene loci have been investigated as potential COPD genetic determinants by case-control genetic association studies. However, inconsistent results of these association studies have been frequent. Genetic heterogeneity and population stratification are two potential reasons for the conflicting findings between association studies. Linkage analysis studies have recently been published that may identify regions of the genome that contain COPD susceptibility genes. Future investigations of genetic influences in COPD should consider the use of family-based designs for association studies and the study of positional candidate genes within regions of linkage.

Journal Article↗
PubMed2003

Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1.

BACKGROUND: One third of patients with epilepsy have drug-resistant epilepsy, which is associated with an increased risk of death and debilitating psychosocial consequences. Because this form is resistant to multiple antiepileptic drugs, the mode of resistance must be nonspecific, involving drug-efflux transporters such as ATP-binding cassette sub-family B member 1 (ABCB1, also known as MDR1 and P-glycoprotein 170). We hypothesized that the CC genotype at the ABCB1 C3435T polymorphism, which is associated with increased expression of the protein, influences the response to antiepileptic-drug treatment. METHODS: ABCB1 3435 was genotyped in 315 patients with epilepsy, classified as drug-resistant in 200 and drug-responsive in 115, and 200 control subjects without epilepsy. Recently devised methods were used to control for population stratification, and linkage disequilibrium was calculated across the gene. RESULTS: As compared with patients with drug-responsive epilepsy, patients with drug-resistant epilepsy were more likely to have the CC genotype at ABCB1 3435 than the TT genotype (odds ratio, 2.66; 95 percent confidence interval, 1.32 to 5.38; P=0.006). There was no genetic stratification between the two groups of patients. The polymorphism fell within an extensive block of linkage disequilibrium spanning much or all of the gene, implying that the polymorphism may not itself be causal but rather may be linked with the causal variant. CONCLUSIONS: These pharmacogenomic results identify a genetic factor associated with resistance to antiepileptic drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

The -159 C-->T polymorphism of CD14 is associated with nonatopic asthma and food allergy.

BACKGROUND: CD14, the receptor for LPS, plays an important role in innate immunity. A polymorphism in the promotor for CD14, -159 C-->T, has been implicated in atopy. OBJECTIVE: We explored the relationship of this polymorphism with both atopic and nonatopic asthma, as well as with food allergy. METHODS: Patients with asthma and food allergy were recruited along with nonatopic, nonasthmatic control subjects. The -159 C-->T polymorphism was genotyped by using the PCR-based RFLP assay. RESULTS: The -159 T allele was more common among patients with nonatopic asthma and food allergy than among control subjects (chi(2) = 6.03, P =.01 and chi(2) = 4.94; P =.03, respectively). Patients with food allergy had a 4-fold increased odds of having the TT genotype versus carriers of the C allele compared with control subjects (odds ratio [OR] = 3.9, 95% CI = 1.5-10.3), whereas patients with nonatopic asthma had a 3-fold increased odds of having the TT genotype (OR = 3.1 [95% CI = 1.1-9.1]). Controlling for sex differences between groups did not alter this relationship, which remained significant for patients with food allergy (OR = 3.7 [95% CI = 1.4-10.1]) or nonatopic asthma (OR = 2.7 [95% CI = 0.9-8.0]). We performed a stratified analysis, limited to white patients, to reduce population stratification. The relationship with the TT genotype was stronger in white patients with nonatopic asthma (OR = 4.4 [95% CI = 1.3-14.8]) and patients with food allergy (OR = 5.1 [95% CI = 1.6-16.2]), even adjusting for sex differences (OR = 3.9 [95% CI = 1.1-13.5] and OR = 4.6 [95% CI = 1.4-14.8], respectively). CONCLUSIONS: The TT genotype of -159 C-->T CD14 is associated with nonatopic asthma and food allergy, particularly in white subjects. Thus CD14 is a candidate gene specifically for nonatopic asthma and not for asthma in general. This indicates that atopic and nonatopic asthma might be distinct conditions in their genetic predisposition, despite the fact that they are very similar once they have been established.

Adolescent↗
PubMed2006

A dopamine transporter gene functional variant associated with cocaine abuse in a Brazilian sample.

The dopamine (DA) transporter DAT1 is a major target bound by cocaine in brain. We examined the influence of functional genetic variants in DAT1 on cocaine addiction. Repeat polymorphisms, including a 30-bp variable-number tandem repeat (VNTR) in intron 8 (Int8 VNTR) with two common alleles, were genotyped in cocaine-dependent abusers (n = 699) and in controls with no past history of drug abuse (n = 866) from São Paulo, Brazil. Positive association was observed with allele 3 of the Int8 VNTR and cocaine abuse (allele odds ratio = 1.2, 95% confidence interval = 1.01-1.37, P = 0.036; 3/3 homozygote odds ratio = 1.45, 95% confidence interval = 1.18-1.78, P = 0.0008). Population stratification was assessed and did not affect the results. Haplotypic analyses using additional polymorphisms indicated that the Int8 VNTR is responsible for the observed association. Functional analyses in reporter-gene constructs, demonstrated that allele 3 mediates significant (P < 0.05) but small reduced expression compared with the "protective" allele 2. This difference increased when 1 and 10 muM cocaine was added to the cell culture ( approximately 40% reduction of the 3 allele expression versus the 2 allele). The 3 allele also demonstrated approximately 3-fold-increased expression over the 2 allele in response to KCl plus forskolin challenge. We demonstrate a robust association between cocaine dependence and a VNTR allele in SLC6A3, conferring a small but detectable effect, and we show that this VNTR may be functional. This study suggests that DAT1 gene variation may play a role in cocaine dependence etiology.

Adolescent↗
PubMed1993

Microsatellite mapping of the gene causing weaver disease in cattle will allow the study of an associated quantitative trait locus.

A genetic disease in cattle, progressive degenerative myeloencephalopathy (weaver disease), is associated with increased milk production. This association could result from population stratification, from a pleiotropic effect of a single gene, or from linkage disequilibrium between the gene causing weaver disease and a quantitative trait locus (QTL) for milk production. To test these hypotheses, we performed an extensive linkage study in a bovine pedigree segregating for the weaver condition and identified a microsatellite locus (TGLA116) closely linked to the weaver gene (zmax, 8.15; theta, 0.03). TGLA116 and, by extension, the weaver locus were assigned to bovine synteny group 13. This microsatellite can be used to identify weaver carriers, to select against this genetic defect, and to study the effect of the corresponding chromosomal region on milk production in Brown Swiss and other breeds of cattle.

Animals↗
PubMed2005

Lack of association of the CD14 promoter polymorphism--159C/T with Caucasian inflammatory bowel disease.

OBJECTIVE: The inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are multifactorial diseases resulting from a complex interaction of genetic and environmental factors. The recently described CARD15 and TNF-alpha risk alleles are believed to be contributors to disease by disrupting inflammatory pathways via impaired response to bacteria. Other bacterial receptors, such as CD14, may also have a role in disease. A promoter polymorphism (-159C/T) in CD14 has been implicated in IBD in a number of studies. MATERIAL AND METHODS: We have analysed this CD14 promoter polymorphism in probands from 206 multiplex IBD families, 110 sporadic IBD individuals and 189 healthy controls from the Australian population, all of whom are Caucasian. RESULTS: We could not replicate the described association between the CD14-159T allele and CD or UC, nor did we find any evidence for an interaction between the CARD15 or TNF-alpha risk alleles and the CD14-159T allele. CONCLUSIONS: It is possible that the association seen in other studies may be due to population stratification or to the CD14 polymorphism being in linkage with the real disease-causing variant(s).

Australia↗
PubMed2002

Transmission/disequilibrium test when neither parent is available in some families: a non-iterative approach.

BACKGROUND: The transmission/disequilibrium test (TDT) is a simple method of detecting linkage between a marker locus and a disease-susceptibility locus. The test requires genotype data from the affected individuals (the probands) and their parents, the 'case-parents triads'. However, missing data from parents often complicate the situations. Several non-iterative methods, such as the sibling-based TDT, the reconstruction-combined TDT, and the 1-TDT have been proposed to deal with the problem. But when the father, the mother, and other non-proband siblings in a family are all unavailable for study, that family has to be excluded from analysis by any of the above methods. METHODS: The author proposes a new non-iterative method to deal with the situation when the data contain some 'orphaned' probands. The method utilises the complete data from case-parents triads to infer probabilistically the missing parental genotypes, under the assumption that the missingness is independent of genotype and ethnic origin. The methods can be tailored to specific genetic models, such as the gene-dose, dominance, and recessive alternatives. RESULTS: Simulation analysis shows that, under the null hypothesis of no linkage, the proposed method is not prone to produce an excess of false positive results, even in complex situations such as population stratification or assortive mating. Under the linkage alternative, the new method recaptures much of the information that would be lost by discarding the orphaned probands. DISCUSSION: The method provides a way for dealing with the situation where neither parents nor siblings are available in a TDT study.

Algorithms↗
PubMed1998

Genetic association mapping based on discordant sib pairs: the discordant-alleles test.

Family-based tests of association provide the opportunity to test for an association between a disease and a genetic marker. Such tests avoid false-positive results produced by population stratification, so that evidence for association may be interpreted as evidence for linkage or causation. Several methods that use family-based controls have been proposed, including the haplotype relative risk, the transmission-disequilibrium test, and affected family-based controls. However, because these methods require genotypes on affected individuals and their parents, they are not ideally suited to the study of late-onset diseases. In this paper, we develop several family-based tests of association that use discordant sib pairs (DSPs) in which one sib is affected with a disease and the other sib is not. These tests are based on statistics that compare counts of alleles or genotypes or that test for symmetry in tables of alleles or genotypes. We describe the use of a permutation framework to assess the significance of these statistics. These DSP-based tests provide the same general advantages as parent-offspring trio-based tests, while being applicable to essentially any disease; they may also be tailored to particular hypotheses regarding the genetic model. We compare the statistical properties of our DSP-based tests by computer simulation and illustrate their use with an application to Alzheimer disease and the apolipoprotein E polymorphism. Our results suggest that the discordant-alleles test, which compares the numbers of nonmatching alleles in DSPs, is the most powerful of the tests we considered, for a wide class of disease models and marker types. Finally, we discuss advantages and disadvantages of the DSP design for genetic association mapping.

Alleles↗
PubMed1998

A discordant-sibship test for disequilibrium and linkage: no need for parental data.

The sibship disequilibrium test (SDT) is designed to detect both linkage in the presence of association and association in the presence of linkage (linkage disequilibrium). The test does not require parental data but requires discordant sibships with at least one affected and one unaffected sibling. The SDT has many desirable properties: it uses all the siblings in the sibship; it remains valid if there are misclassifications of the affectation status; it does not detect spurious associations due to population stratification; asymptotically it has a chi2 distribution under the null hypothesis; and exact P values can be easily computed for a biallelic marker. We show how to extend the SDT to markers with multiple alleles and how to combine families with parents and data from discordant sibships. We discuss the power of the test by presenting sample-size calculations involving a complex disease model, and we present formulas for the asymptotic relative efficiency (which is approximately the ratio of sample sizes) between SDT and the transmission/disequilibrium test (TDT) for special family structures. For sib pairs, we compare the SDT to a test proposed both by Curtis and, independently, by Spielman and Ewens. We show that, for discordant sib pairs, the SDT has good power for testing linkage disequilibrium relative both to Curtis's tests and to the TDT using trios comprising an affected sib and its parents. With additional sibs, we show that the SDT can be more powerful than the TDT for testing linkage disequilibrium, especially for disease prevalence >.3.

Alleles↗
PubMed1999

Combined linkage and association sib-pair analysis for quantitative traits.

An extension to current maximum-likelihood variance-components procedures for mapping quantitative-trait loci in sib pairs that allows a simultaneous test of allelic association is proposed. The method involves modeling of the allelic means for a test of association, with simultaneous modeling of the sib-pair covariance structure for a test of linkage. By partitioning of the mean effect of a locus into between- and within-sibship components, the method controls for spurious associations due to population stratification and admixture. The power and efficacy of the method are illustrated through simulation of various models of both real and spurious association.

Genetic Linkage↗
PubMed1999

A major quantitative-trait locus for mole density is linked to the familial melanoma gene CDKN2A: a maximum-likelihood combined linkage and association analysis in twins and their sibs.

Important risk factors for melanoma are densely clustered melanocytic nevi (common moles) and mutations in the p16 (CDKN2A) gene. Nevi may be subclassified as raised or flat. In our sample, raised nevi were 27% of the total, and the two kinds had a correlation of.33. Correlations for total-nevus count (TNC) in 153 MZ and 199 DZ twin pairs were.94 and.60, respectively, which are compatible with a very-high degree of genetic determination. We hypothesized that some of the genetic variance might be due to variation in the p16 gene. Analysis of linkage to a highly polymorphic marker (D9S942), located close to p16, detected quantitative-trait-loci (QTL) effects accounting for 27% of variance in TNC, rising to 33% if flat but not raised moles were considered. Total heritability was higher for raised (.69) than for flat (.42) moles, but QTL linkage was 0 for raised moles, whereas it accounted for 80% of the heritability of flat moles; additionally, family environment accounted for only 15% of variance in raised versus 46% in flat moles. These findings suggest that raised and flat nevi have very different etiologies. Longer alleles at D9S942 were associated with higher flat-mole counts, and a novel modification to a within-sibship association test showed that this association is genuine and not due to population stratification, although it accounts for only 1% of total variance. Since germline mutations in the exons of CDKN2A are rare, it is likely that variants in the noncoding regions of this gene, or in another gene nearby, are responsible for this major determinant of moliness and, hence, of melanoma risk.

Child↗
PubMed1999

A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission.

A new transmission/disequilibrium-test statistic is proposed for situations in which transmission is uncertain. Such situations arise when transmission of a multilocus marker haplotype is considered, since haplotype phase is often unknown in a substantial number of instances. Even for single-locus markers, transmission is uncertain if one or both parents are missing. In both these situations, uncertainty may be reduced by the typing of further siblings, whose disease status may be unaffected or unknown. The proposed test is a score test based on a partial score function that omits the terms most influenced by hidden population stratification.

Adult↗
PubMed2000

The transmission/disequilibrium test and parental-genotype reconstruction for X-chromosomal markers.

Family-based association methods have recently been introduced that allow testing for linkage in the presence of linkage disequilibrium between a marker and a disease even if there is only incomplete parental-marker information. No such tests are currently available for X-linked markers. This report fills this methodological gap by presenting the X-linked sibling transmission/disequilibrium test (XS-TDT) and the X-linked reconstruction-combination transmission/disequilibrium test (XRC-TDT). As do their autosomal counterparts (S-TDT and RC-TDT), these tests make no assumption about the mode of inheritance of the disease and the ascertainment of the sample. They protect against spurious association due to population stratification. The two tests were compared by simulations, which show that (1) the X-linked RC-TDT is, in general, considerably more powerful than the X-linked S-TDT and (2) the lack of parental-genotype information can be offset by the typing of a sufficient number of sibling controls. A freely available SAS implementation of these tests allows the calculation of exact P values.

Alleles↗
PubMed2000

Detection of disease genes by use of family data. I. Likelihood-based theory.

We present a class of likelihood-based score statistics that accommodate genotypes of both unrelated individuals and families, thereby combining the advantages of case-control and family-based designs. The likelihood extends the one proposed by Schaid and colleagues (Schaid and Sommer 1993, 1994; Schaid 1996; Schaid and Li 1997) to arbitrary family structures with arbitrary patterns of missing data and to dense sets of multiple markers. The score statistic comprises two component test statistics. The first component statistic, the nonfounder statistic, evaluates disequilibrium in the transmission of marker alleles from parents to offspring. This statistic, when applied to nuclear families, generalizes the transmission/disequilibrium test to arbitrary numbers of affected and unaffected siblings, with or without typed parents. The second component statistic, the founder statistic, compares observed or inferred marker genotypes in the family founders with those of controls or those of some reference population. The founder statistic generalizes the statistics commonly used for case-control data. The strengths of the approach include both the ability to assess, by comparison of nonfounder and founder statistics, the potential bias resulting from population stratification and the ability to accommodate arbitrary family structures, thus eliminating the need for many different ad hoc tests. A limitation of the approach is the potential power loss and/or bias resulting from inappropriate assumptions on the distribution of founder genotypes. The systematic likelihood-based framework provided here should be useful in the evaluation of both the relative merits of case-control and various family-based designs and the relative merits of different tests applied to the same design. It should also be useful for genotype-disease association studies done with the use of a dense set of multiple markers.

Alleles↗
PubMed2000

Unbiased application of the transmission/disequilibrium test to multilocus haplotypes.

When the transmission/disequilibrium test (TDT) is applied to multilocus haplotypes, a bias may be introduced in some families for which both parents have the same heterozygous genotype at some locus. The bias occurs because haplotypes can only be deduced from certain offspring, with the result that the transmissions of the two parental haplotypes are not independent. We obtain an unbiased TDT for individual haplotypes by calculating the correct variance for the transmission count within a family, using information from multiple siblings if they are available. An existing correction for dependence between siblings in the presence of linkage is retained. To obtain an unbiased multihaplotype TDT, we must either count transmissions from one randomly chosen parent or count all transmissions and estimate the significance level empirically. Alternatively, we may use missing-data techniques to estimate uncertain haplotypes, but these methods are not robust to population stratification. An illustration using data from the insulin-gene region in type 1 diabetes shows that the validity and power of the TDT may vary by an order of magnitude, depending on the method of analysis.

Bias↗
PubMed2000

Transmission/disequilibrium tests using multiple tightly linked markers.

Transmission/disequilibrium tests have attracted much attention in genetic studies of complex traits because (a) their power to detect genes having small to moderate effects may be greater than that of other linkage methods and (b) they are robust against population stratification. Highly polymorphic markers have become available throughout the human genome, and many such markers can be studied within short physical distances. Studies using multiple tightly linked markers are more informative than those using single markers. However, such information has not been fully utilized by existing statistical methods, resulting in possibly substantial loss of information in the identification of genes underlying complex traits. In this article, we propose novel statistical methods to analyze multiple tightly linked markers. Simulation studies comparing our methods versus existing methods suggest that our methods are more powerful. Finally, we apply the proposed methods to study genetic linkage between the dopamine D2 receptor locus and alcoholism.

Alcoholism↗
PubMed2003

Studying parents and grandparents to assess genetic contributions to early-onset disease.

Suppose DNA is available from affected individuals, their parents, and their grandparents. Particularly for early-onset diseases, maternally mediated genetic effects can play a role, because the mother determines the prenatal environment. The proposed maximum-likelihood approach for the detection of apparent transmission distortion treats the triad consisting of the affected individual and his or her two parents as the outcome, conditioning on grandparental mating types. Under a null model in which the allele under study does not confer susceptibility, either through linkage or directly, and when there are no maternally mediated genetic effects, conditional probabilities for specific triads are easily derived. A log-linear model permits a likelihood-ratio test (LRT) and allows the estimation of relative penetrances. The proposed approach is robust against genetic population stratification. Missing-data methods permit the inclusion of incomplete families, even if the missing person is the affected grandchild, as is the case when an induced abortion has followed the detection of a malformation. When screening multiple markers, one can begin by genotyping only the grandparents and the affected grandchildren. LRTs based on conditioning on grandparental mating types (i.e., ignoring the parents) have asymptotic relative efficiencies that are typically >150% (per family), compared with tests based on parents. A test for asymmetry in the number of copies carried by maternal versus paternal grandparents yields an LRT specific to maternal effects. One can then genotype the parents for only the genes that passed the initial screen. Conditioning on both the grandparents' and the affected grandchild's genotypes, a third log-linear model captures the remaining information, in an independent LRT for maternal effects.

Age of Onset↗
PubMed2003

Undetected genotyping errors cause apparent overtransmission of common alleles in the transmission/disequilibrium test.

The transmission/disequilibrium test (TDT), a family-based test of linkage and association, is a popular and intuitive statistical test for studies of complex inheritance, as it is nonparametric and robust to population stratification. We carried out a literature search and located 79 significant TDT-derived associations between a microsatellite marker allele and a disease. Among these, there were 31 (39%) in which the most common allele was found to exhibit distorted transmission to affected offspring, implying that the allele may be associated with either susceptibility to or protection from a disease. In 27 of these 31 studies (87%), the most common allele appeared to be overtransmitted to affected offspring (a risk factor), and, in the remaining 4 studies, the most common allele appeared to be undertransmitted (a protective factor). In a second literature search, we identified 92 case-control studies in which a microsatellite marker allele was found to have significantly different frequencies in case and control groups. Of these, there were 37 instances (40%) in which the most common allele was involved. In 12 of these 37 studies (32%), the most common allele was enriched in cases relative to controls (a risk factor), and, in the remaining 25 studies, the most common allele was enriched in controls (a protective factor). Thus, the most common allele appears to be a risk factor when identified through the TDT, and it appears to be protective when identified through case-control analysis. To understand this phenomenon, we incorporated an error model into the calculation of the TDT statistic. We show that undetected genotyping error can cause apparent transmission distortion at markers with alleles of unequal frequency. We demonstrate that this distortion is in the direction of overtransmission for common alleles. Therefore, we conclude that undetected genotyping errors may be contributing to an inflated false-positive rate among reported TDT-derived associations and that genotyping fidelity must be increased.

Alleles↗