Papers by Joe Terwilliger
Anthropological Genetics
Page 50. Chapter 3 Natural Experiments in Human Gene Mapping: The Intersection of Anthropological... more Page 50. Chapter 3 Natural Experiments in Human Gene Mapping: The Intersection of Anthropological Genetics and Genetic Epidemiology Joseph QTerwilliger Department of Psychiatry, Department of Genetics and Development ...
Genetic Research in Psychiatry, 1992
Linkage analysis refers to that branch of genetics in which the recombination fraction θ between ... more Linkage analysis refers to that branch of genetics in which the recombination fraction θ between two loci is estimated, where θ = 1/2 represents free recombination (absence of linkage) and θ < 1/2 refers to linkage. In human linkage analysis, the evidence for linkage between a trait and a marker (or a map of markers) is generally summarized by the maximum logarithm of odds (lod) score, Zmax. Conventionally, if Zmax attains or exceeds the value 3, linkage is said to be “proven.” Such a “proof,” however, is of a statistical nature — a Zmax value of 3 or more may occur by chance (without linkage) although this is very unlikely. Given that no linkage exists, the probability (the so-called p value) of finding a maximum lod score equal to or exceeding Z is no larger than 10−Z (Morton 1978; see also discussion in Ott 1991).
Advances in Genetics, 2001
ABSTRACT Before contemplating a genome scan to identify the map position of disease-predisposing ... more ABSTRACT Before contemplating a genome scan to identify the map position of disease-predisposing genes, an investigator should have prior evidence of the genes&#39; existence. It is therefore logically consistent to evaluate a genome scan experiment as an estimation problem, rather than as a hypothesis-testing problem, since absent prior evidence of the existence of disease genes, it is probably unwise to conduct the experiment at all. Recombination in a single meiosis can be modeled as a point process along the chromosome, and linkage or linkage disequilibrium (LD) mapping statistics are a simple function of the superposition of the recombination processes occurring in all meioses under study. Thus, multipoint lod scores are shown to be step functions, in the absence of ambiguity about the inheritance of chromosomal segments. The ability to map a disease gene is a function of how well the ascertained phenotypes predict the underlying trait locus genotypes. This chapter presents a thorough investigation of the properties of the multipoint lod score and uses results from renewal theory to examine the effects of deviations from a deterministic phenotype-genotype relationship. The quality of estimated gene locations is assessed through computing the mean and variance of the length of the expected 3-lod-unit support interval around the maximum likelihood estimate. The more deterministic the model, the smaller this interval is. A more exact quantification of details of this effect is used to describe the statistical properties of such genome scanning experiments from the perspective of estimation, with appropriately little regard to hypothesis testing. Hypothesis testing, however, is discussed as an appropriate context to describe linkage and LD analysis in situations where candidate genes are being screened, since only there does one have definable null and alternative hypotheses that have not been rejected before the beginning of the experiment. By contrast, it is hoped that the null hypothesis &quot;there is no gene affecting this phenotype&quot; has been rejected by other means before an expensive genome scan is even contemplated (though that this is often not done is probably the main problem!).
American journal of human genetics, 1996
Letters to the Editor 1093 twofold increased risk nearly 85% of the time. This is clearly unaccep... more Letters to the Editor 1093 twofold increased risk nearly 85% of the time. This is clearly unacceptable in a positional cloning project. While the precise numbers change, the general conclusion applies to all types of meiotic mapping data. The simple argument presented above underscores the difficulty of finely mapping genes underlying complex traits. This situation is in contrast to that of a rare simple Mendelian trait, for which the gene always lies in the region of maximal sharing delimited by the closest flanking recombinants. Complex traits are different because a single recombinant cannot be trusted to rule out a region as the gene's location-the observed lack of allele sharing may instead reflect the fact that an affected individual happens not to carry the susceptibility gene.
Wiley StatsRef: Statistics Reference Online, 2014
Psychiatric Genetics, 1995
Genetic Epidemiology, 1993
A novel approach to combining data from multiple linked loci is proposed that can provide substan... more A novel approach to combining data from multiple linked loci is proposed that can provide substantial increases in power over normal two‐point linkage analysis or sib‐pair analysis, with a substantial saving in computing time over traditional multipoint methods. © 1993 Wiley‐Liss, Inc.
British Journal of Psychiatry, 1991
The hypothesis that at least a subgroup of familial cases of schizophrenia could be due to a gene... more The hypothesis that at least a subgroup of familial cases of schizophrenia could be due to a genetic defect on the X chromosome is supported by the observation of an excess of X-chromosome aneuploidies (XXX and XXY) among populations of patients with psychosis. The distal long arm, Xq27–q28, is a candidate region where linkage has been claimed to manic-depressive disorder and a fragile site has been associated with schizophrenia spectrum disorders. The present study excluded linkage to a large part of this region using four polymorphic probes and multipoint lod-score analysis in 10 families with multiple members with schizophrenia.
Annals of Medicine, 2003
Many promises have been made about the impact of the Human Genome Project on clinical practice an... more Many promises have been made about the impact of the Human Genome Project on clinical practice and public health, yet despite massively funded efforts over the past decade, little headway has been made in elucidating the specific genetic factors which have major impact on the risk of developing common complex traits. There are two fundamental reasons for this abject failure as follows: 1) studies have been inadequately designed to identify such genetic risk factors; 2) the genetic factors that do exist are individually of small marginal importance, and are characterized by extensive heterogeneity. If 2) is the truth, there is little we can do about it, so we emphasize the importance of 1) in this article, while recognizing that 2) probably is not far from the truth. Genetic studies, in contrast to epidemiological studies, use confounding and ascertainment bias to help identify weak etiologic signal due to genes, since gene mapping is fundamentally a hypothesis-free science. This strategy makes it possible to identify genetic risk factors, but makes it impossible to quantify the size of their effect on risk. Classical epidemiological study designs are of minimal value for gene identification, but may be of use in estimation of the effect size of genetic risk factors once they are identified in more appropriately designed genetic studies. However, if the effects are so weak that we need this strong, systematic ascertainment bias to find them, their relevance to public health may be of questionable immediate value, raising many questions about the rhetoric and promises being made to the public as justification for &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;big science&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; approaches to dissecting the hypothetical role of genes in complex traits.
A novel procedure for detecting linkage disequilibrium is proposed which has only one degree of f... more A novel procedure for detecting linkage disequilibrium is proposed which has only one degree of freedom irrespective of the number of alleles at the marker locus under consideration. In this test, all marker allele frequencies are determined as a function of the true marker allele frequencies, the recombination fraction between marker and disease, and the number of generations since an initial disease mutation was introduced into the population. Under the restrictive assumption of one initial founder mutation occuring in the population under study, it is possible to predict the marker allele frequency in the case sample as follows: p{sub n}=p{sub n{minus}1}(1-{theta}) + q{sub n{minus}1}{theta}, where p{sub n} is the frequency in the case sample of the allele in generation n, and q{sub n} is the frequency of said marker allele in the control sample. Then a test of linkage disequilibrium can be parametrized as a function of {theta} using a {open_quotes}LOD{close_quotes} score statistic as log{sub 10}[L({theta})/L({theta}=0.5)], where the allele frequencies in generation 0, and the number of generations since introduction of the allele to the population are treated as nuisance parameters and estimated separately in numerator and denominator, thus leaving us with a test statistic on one df, irrespective ofmore » the number of alleles at the marker locus. While the assumptions are often not reasonable, violations of said assumptions will simply have the effect of making the test less powerful. Still, the test is consistently more powerful than the standard 2 x n table chi-square test of association for multi-allelic marker systems. Multiple founders, non-zero mutation rates, and an extension to multipoint association tests are under development.« less
Fine mapping of a second locus involved in susceptibility for systemic lupus erythematosus on chr... more Fine mapping of a second locus involved in susceptibility for systemic lupus erythematosus on chromosome 4p in Icelandic pedigrees
American Journal of Medical Genetics, 1991
The clinical similarity with the X‐linked muscular dystrophies and the uniqueness of the homology... more The clinical similarity with the X‐linked muscular dystrophies and the uniqueness of the homology between the DMD‐like and the 1.8 kb sequeces at the carboxyterminal domain of the dystrophin gene led to the suggestion that this 6q sequence might be a strong candidate for one of the autosomal recessive muscular dystrophies. Thus, we tested, through linkage analysis, if 6q probes flanking the dystrophin‐homologous sequence are linked to the gene responsible for limb‐girdle dystrophy (LGMD).A total of 226 individuals (57 patients and 169 unaffected relatives) from 19 large unrelated Brazilian families was studied.Results of two‐point aalysis excluded linkage with MYB (6q22–23) and ESR (6q24–q27) at θ=0.10 and with TCP1 (6q25–q27) at θ=0.05, indicating that the LGMD gene is not in the 6q23–q27 region. Therefore, the dystrophin‐homologue sequence is not the gene responsible for LGMD.
Alzheimer's & Dementia, 2018
East Asians and it was found to be stronger than Caucasians. . To address the underlying causal f... more East Asians and it was found to be stronger than Caucasians. . To address the underlying causal factors for these ethnicity-dependent difference, we screened the polymorphisms near APOE gene by assessing allele frequency and statistical analysis and found that some SNPs exhibit ε4/ε4-mediated risk for Alzheimer’s disease. Conclusions:In our study, we show that the e4/4 carriers were more vulnerable to AD in East Asian populations rather than Caucasians and Africans. Furthermore, the East Asians are highly prone to e4/4dependent atrophy in the cortical thickness and hippocampal volume compared to Caucasians. A polymorphism in the APOE promoter can modulate APOE e4-mediated risk for Alzheimer’s disease.
Alzheimer's & Dementia, 2018
gender, education, chronic disease count, social network index, anticholinergic cognitive burden ... more gender, education, chronic disease count, social network index, anticholinergic cognitive burden (ACB) score, Apoε4 status and antipsychotic drug use. Results: The best fitting model contained two classes; class 1 was the largest (N1⁄4389, 76%) and showed the slowest progression on both MMSE and ADL (figures 1 and 2; blue curves). Individuals in class 2 (N1⁄4123, 24%) demonstrated more rapid worsening on both outcomes (red curves), often followed by death within 5 years after dementia diagnosis (N1⁄494). Significant predictors of membership in the rapidly declining class 2, relative to class 1, were higher ACB score (OR1⁄41.35, 95%-CI: 1.01-1.81) and higher age (OR1⁄41.10, 95%-CI: 1.00-1.20). Conclusions: Our study shows that most individuals were members of a class with relatively slow disease progression. This presents a more optimistic prospect for the majority of patients as compared to the mean progression rate of the entire sample. This is important for informing newly diagnosed dementia patients and their caregivers about the course of the disease. The observed relationship between ACB and rapid decline in cognition and functioning urges caution in prescribing anticholinergic drugs and polypharmacy for individuals with dementia. This is especially relevant given that most antipsychotics used in dementia have a high ACB score.
JMM case reports, 2018
The abstract states 'a child of 4 years of age with retrobulbar uveitis', this should be 'a child... more The abstract states 'a child of 4 years of age with retrobulbar uveitis', this should be 'a child of 4 years of age with retrobulbar neuritis'. The author apologizes for any inconvenience caused.
JMM case reports, 2018
Although the current Zika virus (ZIKV) epidemic is a major public health concern, most reports ha... more Although the current Zika virus (ZIKV) epidemic is a major public health concern, most reports have focused on congenital ZIKV syndrome, its most devastating manifestation. Severe ocular complications associated with ZIKV infections and possible pathogenetic factors are rarely described. Here, we describe three Venezuelan patients who developed severe ocular manifestations following ZIKV infections. We also analyse their serological response to ZIKV and dengue virus (DENV). One adult with bilateral optic neuritis, a child of 4 years of age with retrobulbar uveitis and a newborn with bilateral congenital glaucoma had a recent history of an acute exanthematous infection consistent with ZIKV infection. The results of ELISA tests indicated that all patients were seropositive for ZIKV and four DENV serotypes. Patients with ZIKV infection can develop severe ocular complications. Anti-DENV antibodies from previous infections could play a role in the pathogenesis of these complications. Wel...
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Papers by Joe Terwilliger