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Susan E Hodge

Publications and source records attributed to Susan E Hodge.

10 recordsLinked to original sources
PubMed2003

Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q.

Substantial evidence supports that there is a genetic component to panic disorder (PD). Until recently, attempts at localizing genes for PD by using standard phenotypic data have not proven successful. Previous work suggests that a potential subtype of PD called the panic syndrome exists, and it is characterized by a number of medical conditions, most notably bladder/renal disorders. In the current study, a genome scan with 384 microsatellite markers was performed on 587 individuals in 60 multiplex pedigrees segregating PD and bladder/kidney conditions. Using both single-locus and multipoint analytic methods, we found significant linkage on chromosome 22 (maximum heterogeneity logarithm of odds score = 4.11 at D22S445) and on chromosome 13q (heterogeneity logarithm of odds score = 3.57 at D13S793) under a dominant-genetic model and a broad phenotypic definition. Multipoint analyses did not support the observation on chromosome 22. The chromosome 13 findings were corroborated by multipoint findings, and extend our previous findings from 19 of the 60 families. Several other regions showed elevated scores by using when one analytic method was used, but not the other. These results suggest that there are genes on chromosome 13q, and possibly on chromosome 22 as well, that influence the susceptibility toward a pleiotropic syndrome that includes PD, bladder problems, severe headaches, mitral valve prolapse, and thyroid conditions.

Chromosome Mapping↗
PubMed2003

Sex-specific mutation rates for x-linked disorders: estimation and application.

Emerging human molecular data are adding to our knowledge about the frequency and pattern of genetic mutations. This not only gives important insight into the biological processes underlying mutation, but also provides data which must be incorporated in the clinical setting. An example is the assumption of equal mutation probability in the male and female germ lines. This is a key assumption in Bayesian risk calculation for families segregating an X-linked recessive disorder. For some disorders, data are now available that demonstrate that the mutation probability in males differs from that in females. In this paper, we review the estimation of the male-female mutation rate ratio, including the construction of confidence intervals, and apply sex-specific mutation rates to carrier risk calculation in a variety of pedigree structures. In several instances, the difference in risk is substantial.

Chromosomes, Human, X↗
PubMed2002

Evidence for a susceptibility locus for panic disorder near the catechol-O-methyltransferase gene on chromosome 22.

BACKGROUND: A well-characterized single nucleotide polymorphism (472G/A-Val/Met-SNP8) in the coding sequence of the catechol-O-methyltransferase (COMT) gene leads to a three- to fourfold difference in enzymatic activity and clinical and animal studies suggest a role in anxiety states like panic disorder. METHODS: Subjects from 70 panic disorder pedigrees, and 83 "triads", were genotyped at seven single nucleotide polymorphisms (SNPs), polymorphic microsatellites in the first intron of COMT and approximately 339kb upstream of COMT (D22S944) and analyzed for genetic association and linkage. RESULTS: Linkage analysis showed elevated LOD scores for 472G/A (SNP 8), silent exon 3 substitution (186C/T-SNP 5), and the marker D22S944 (2.88, 2.62, and 2.93, respectively), using a variety of diagnostic and genetic models. Association tests were not significant for the SNPs, but were highly significant for D22S944 (p =.0001-.0003). One three-marker haplotype formed from the above three polymorphisms was significantly associated with panic disorder (p =.0001), as was the "global" p value for this combination (p =.005). In addition, numerous haplotypes with combinations of D22S944 and COMT SNPs were found to be significantly associated with panic disorder. CONCLUSIONS: Our findings provide strong evidence for a susceptibility locus for panic disorder either within the COMT gene or in a nearby region of chromosome 22.

Adult↗
PubMed2002

Possible association of NTDs with a polyhistidine tract polymorphism in the ZIC2 gene.

Neural tube defects (NTDs) and brain malformations represent a common finding in chromosome 13q deletion patients. Hemizygosity for ZIC2, which is located in the 13q32 critical deletion region, results in holoprosencephaly (HPE) in humans, and diminished expression of ZIC2 results in HPE as well as lumbosacral NTDs in mice. Taken together, these observations led us to hypothesize that ZIC2 mutations may be a cause of isolated NTD. To test this, we screened 192 NTD patients for mutations in ZIC2. While we did not find ZIC2 mutations in these patients, we did find some evidence of a possible association between a histidine tract polymorphism in ZIC2 and NTDs. Our sample was too small to reach definitive conclusions, but the evidence is sufficiently intriguing to encourage further research. If this association is confirmed, subtle alterations in ZIC2 activity may confer a risk of NTD.

Alleles↗
PubMed2002

Quantification of type I error probabilities for heterogeneity LOD scores.

Locus heterogeneity is a major confounding factor in linkage analysis. When no prior knowledge of linkage exists, and one aims to detect linkage and heterogeneity simultaneously, classical distribution theory of log-likelihood ratios does not hold. Despite some theoretical work on this problem, no generally accepted practical guidelines exist. Nor has anyone rigorously examined the combined effect of testing for linkage and heterogeneity and simultaneously maximizing over two genetic models (dominant, recessive). The effect of linkage phase represents another uninvestigated issue. Using computer simulation, we investigated type I error (P value) of the "admixture" heterogeneity LOD (HLOD) score, i.e., the LOD score maximized over both recombination fraction theta and admixture parameter alpha and we compared this with the P values when one maximizes only with respect to theta (i.e., the standard LOD score). We generated datasets of phase-known and -unknown nuclear families, sizes k = 2, 4, and 6 children, under fully penetrant autosomal dominant inheritance. We analyzed these datasets (1) assuming a single genetic model, and maximizing the HLOD over theta and alpha; and (2) maximizing the HLOD additionally over two dominance models (dominant vs. recessive), then subtracting a 0.3 correction. For both (1) and (2), P values increased with family size k; rose less for phase-unknown families than for phase-known ones, with the former approaching the latter as k increased; and did not exceed the one-sided mixture distribution xi = (1/2) chi1(2) + (1/2) chi2(2). Thus, maximizing the HLOD over theta and alpha appears to add considerably less than an additional degree of freedom to the associated chi1(2) distribution. We conclude with practical guidelines for linkage investigators.

Chi-Square Distribution↗
PubMed2002

Relative risk for genetic associations: the case-parent triad as a variant of case-cohort design.

The contribution of this paper is to conceptualize the case-parent triad within an epidemiological framework. We propose that the case-parent triad design is a variant of the case-cohort design. The affected offspring of case-parent triads come from a source cohort of all offspring of parents in a population. We first demonstrate that if the source cohort is restricted to offspring of a certain parental mating type then the relative risk in relation to genetic exposure can be estimated simply from the ratio of the number of exposed to the number of unexposed affected offspring. We then extend the logic to studies including offspring of all parental mating types; provided that the allele frequencies and possible parental mating types are specified, a valid relative risk can still be estimated. Compared to prior descriptions of the case-parent triad design, the proposed approach is readily understandable, epidemiologically meaningful and provides a relatively simple perspective for estimating valid measure of effect. Also, by allowing the potential sources of selection bias to be revealed more easily the design is made more accessible both conceptually and practically to epidemiologists.

Case-Control Studies↗
PubMed2001

Likelihood formulation of parent-of-origin effects on segregation analysis, including ascertainment.

We developed a likelihood-based method for testing for parent-of-origin effect in complex diseases. The likelihood formulations model parent-of-origin effect and allow for incorporation of ascertainment, as well as differential male and female ascertainment probabilities. The results based on simulated data indicated that the estimates of parental effect (either maternal or paternal) were biased when ascertainment was ignored or when the wrong ascertainment model was used. The exception was single ascertainment, in which we proved that ignoring ascertainment does not bias the estimation of parental effect, in a simple parent-of-origin model. These results underscore the importance of considering ascertainment models when testing for parent-of-origin effect in complex diseases.

Bias↗