David A Greenberg - Academia.edu (original) (raw)

Papers by David A Greenberg

Annals of Clinical and Translational Neurology, 2020

Objective: Impulsivity is a multidimensional construct that can predispose to psychopathology. Me... more Objective: Impulsivity is a multidimensional construct that can predispose to psychopathology. Meta-analysis demonstrates an association between response impulsivity and Juvenile Myoclonic Epilepsy (JME), a common genetic generalized epilepsy. Here, we test the hypotheses that trait impulsivity is (i) elevated in JME compared to controls; (ii) moderated by specific seizure characteristics; and (iii) associated with psychiatric adverse effects of antiepileptic drugs (AEDs). Methods: 322 participants with JME and 126 age and gender-matched controls completed the Barratt's Impulsiveness Scale (BIS-brief) alongside information on seizure history and AED use. We compared group BIS-brief scores and assessed associations of JME BIS-brief scores with seizure characteristics and AED adverse effects. Results: The mean BIS-brief score in JME was 18.1 AE 4.4 compared with 16.2 AE 4.1 in controls (P = 0.0007). Elevated impulsivity was associated with male gender (P = 0.027), frequent absence seizures (P = 0.0004) and lack of morning predominance of myoclonus (P = 0.008). High impulsivity significantly increased the odds of a psychiatric adverse event on levetiracetam (P = 0.036), but not any other psychiatric or somatic adverse 138

American journal of human genetics, 1996

American journal of human genetics, 1993

American journal of human genetics, 1982

There appear to be several alleles of the hexosaminidase A (HEX A) gene that lead to different cl... more There appear to be several alleles of the hexosaminidase A (HEX A) gene that lead to different clinical syndromes. In addition to the infantile-onset Tay-Sachs disease (TSD), there is a juvenile-onset and an adult-onset form, which are also characterized by low HEX A levels. There are also apparently healthy adults with low HEX A activity. Based primarily on data from population screening for TSD carrier status, we estimate the allele frequency of the combined variant alleles for which data are available to be about 4.5 x 10(-4) and the frequency of adults showing zero HEX A levels (when tested using artificial substrate) to be about 1:67,000. The implications for population screening and prenatal diagnosis are discussed.

American journal of human genetics, 1986

In many family studies, it is often difficult to know exactly how the families were ascertained. ... more In many family studies, it is often difficult to know exactly how the families were ascertained. Even if known, the circumstances under which the families came to the attention of the study may violate the assumptions of classical ascertainment bias correction. The purpose of this work was to investigate the effect on segregation analysis of violations of the assumptions of the classical ascertainment model. We simulated family data generated under a simple recessive model of inheritance. We then ascertained families under different "scenarios." These scenarios were designed to simulate actual conditions under which families come to the attention of-and then interact with-a clinic or genetic study. We show that how one designates probands, which one must do under the classical ascertainment model, can influence parameter estimation and hypothesis testing. We demonstrate that, in some cases, there may be no "correct" way to designate probands. Further, we show tha...

Proceedings of the National Academy of Sciences, 2008

Hashimoto's thyroiditis (HT) is associated with HLA, but the associated allele is still contr... more Hashimoto's thyroiditis (HT) is associated with HLA, but the associated allele is still controversial. We hypothesized that specific HLA-DR pocket-sequence variants are associated with HT and that similar variants in the murine I-E locus (homologous to HLA-DR) predispose to experimental autoimmune thyroiditis (EAT), a classical mouse model of HT. Therefore, we sequenced the polymorphic exon 2 of the HLA-DR gene in 94 HT patients and 149 controls. In addition, we sequenced exon 2 of the I-E gene in 22 strains of mice, 12 susceptible to EAT and 10 resistant. Using logistic regression analysis, we identified a pocket amino acid signature, Tyr-26, Tyr-30, Gln-70, Lys-71, strongly associated with HT ( P = 6.18 × 10 −5 , OR = 3.73). Lys-71 showed the strongest association ( P = 1.7 × 10 −8 , OR = 2.98). This association was seen across HLA-DR types. The 5-aa haplotype Tyr-26, Tyr-30, Gln-70, Lys-71, Arg-74 also was associated with HT ( P = 3.66 × 10 −4 ). In mice, the I-E pocket amino...

Osteoporosis International, 2007

Animal models suggest a role for osteonectin/SPARC in determination of bone mass. We found haplot... more Animal models suggest a role for osteonectin/SPARC in determination of bone mass. We found haplotypes consisting of three single nucleotide polymorphisms (SNPs) in the 3′ untranslated region (UTR) of the osteonectin gene are associated with bone density in Caucasian men with idiopathic osteoporosis. Introduction-Osteonectin is a matricellular protein regulating matrix assembly, osteoblast differentiation, and survival. Animal studies indicate that osteonectin is essential for normal bone mass. The 3′ UTR is a regulatory region controlling mRNA stability, trafficking, and translation, and we determined whether osteonectin 3′ UTR haplotypes could be associated with bone mass and/or idiopathic osteoporosis. Methods-Single strand conformation polymorphism and allele-specific PCR analysis were used to assess alleles at osteonectin cDNA bases 1046, 1599, and 1970, using genomic DNA from middleaged Caucasian men with idiopathic, low turnover osteoporosis (n=56) and matched controls (n=59). Bone density was measured by DXA at spine, hip and radius. Allele and haplotype frequencies were analyzed by Chi square analysis and Fisher's exact test. Results-Five common osteonectin 3′ UTR haplotypes were identified. The frequency of one haplotype (1046C-1599C-1970T) was higher in controls compared with patients, and this haplotype was also associated with higher bone densities at multiple sites in patients. In contrast, a second haplotype (1046C-1599G-1970T) was associated with lower bone densities in patients at multiple sites. Conclusions-Osteonectin regulates skeletal remodeling and bone mass in animals, and haplotypes in the 3′ UTR of this gene are associated with bone density in Caucasian men with idiopathic osteoporosis.

Journal of Biological Chemistry, 2011

Autoimmune thyroid diseases (AITD) arise from complex interactions between genetic, epigenetic, a... more Autoimmune thyroid diseases (AITD) arise from complex interactions between genetic, epigenetic, and environmental factors. Whole genome linkage scans and association studies have established thyroglobulin (TG) as a major AITD susceptibility gene. However, the causative TG variants and the pathogenic mechanisms are unknown. Here, we describe a genetic/ epigenetic mechanism by which a newly identified TG promoter single-nucleotide polymorphism (SNP) variant predisposes to AITD. Sequencing analyses followed by case control and familybased association studies identified an SNP (؊1623A3 G) that was associated with AITD in the Caucasian population (p ‫؍‬ 0.006). We show that the nucleotide substitution introduced by SNP (؊1623A/G) modified a binding site for interferon regulatory factor-1 (IRF-1), a major interferon-induced transcription factor. Using chromatin immunoprecipitation, we demonstrated that IRF-1 binds to the 5 TG promoter motif, and the transcription factor binding correlates with active chromatin structure and is marked by enrichment of mono-methylated Lys-4 residue of histone H3, a signature of active transcriptional enhancers. Using reporter mutations and siRNA approaches, we demonstrate that the disease-associated allele (G) conferred increased TG promoter activity through IRF-1 binding. Finally, treatment of thyroid cells with interferon ␣, a known trigger of AITD, increased TG promoter activity only when it interacted with the disease-associated variant through IRF-1 binding. These results reveal a new mechanism of interaction between environmental (IFN␣) and genetic (TG) factors to trigger AITD. Autoimmune thyroid diseases (AITD), 4 including Graves disease (GD) and Hashimoto thyroiditis (HT), are character

Human Heredity, 2004

Human recombination fraction (RF) can differ between males and females, but investigators do not ... more Human recombination fraction (RF) can differ between males and females, but investigators do not always know which disease genes are located in genomic areas of large RF sex differences. Knowledge of RF sex differences contributes to our understanding of basic biology and can increase the power of a linkage study, improve gene localization, and provide clues to possible imprinting. One way to detect these differences is to use lod scores. In this study we focused on detecting RF sex differences and answered the following questions, in both phase-known and phase-unknown matings: (1) How large a sample size is needed to detect a RF sex difference? (2) What are ‘optimal’ proportions of paternally vs. maternally informative matings? (3) Does ascertaining nonoptimal proportions of paternally or maternally informative matings lead to ascertainment bias? Our results were as follows: (1) We calculated expected lod scores (ELODs) under two different conditions: ‘unconstrained,’ allowing sex-...

American Journal of Medical Genetics, 1983

One hundred families with insulin-dependent diabetes mellitus (IDDM) were analyzed for linkage wi... more One hundred families with insulin-dependent diabetes mellitus (IDDM) were analyzed for linkage with 27 genetic markers, including HLA, properdin factor B (BF), and glyoxalase 1 (GLO) on chromosome 6, and Kidd blood group (Jk) on chromosome 2. The linkage analyses were performed under several different genetic models. An approximate correction for two-locus linkage analysis was developed and applied to four markers. Two different heterogeneity tests were implemented and applied to all the markers. One, the Predivided-Sample Test, utilizes various criteria thought to be relevant to genetic heterogeneity in IDDM. The other, the Admixture Test, looks for heterogeneity without specifying a priori how the sample should be divided. Results continued to support linkage of IDDM with three chromosome 6 markers: HLA, BF, and GLO. The total lod score for Kidd blood group, under the recessive model with 20% penetrance, is 1.63-down 1.2 from the 2.83 reported by us earlier. The only other marker whose lod score exceeded 1.0 under any model was pancreatic amylase (AMY2). The two-locus correction, which involved lowering the penetrance values used in the analysis, affected estimates of 0 (recombination fraction) but did not markedly change the lod scores themselves. There was little evidence for heterogeneity within any of the lod scores, under either the Predivided-Sample Test or the Admixture Test.

The American Journal of Human Genetics, 2001

Annals of Neurology, 2001

Idiopathic generalized epilepsy (IGE) is a common, complex disease with an almost exclusively gen... more Idiopathic generalized epilepsy (IGE) is a common, complex disease with an almost exclusively genetic etiology but with variable phenotypes. Clinically, IGE can be divided into different syndromes. Varying lines of evidence point to the involvement of several interacting genes in the etiology of IGE. We performed a genome scan in 91 families ascertained through a proband with adolescent-onset IGE. The IGEs included juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), and epilepsy with generalized tonic clonic seizures (EGTCS). Our linkage results support an oligogenic model for IGE, with strong evidence for a locus common to most IGEs on chromosome 18 (lod score 4.4/5.2 multipoint/ two-point) and other loci that may influence specific seizure phenotypes for different IGEs: a previously identified locus on chromosome 6 for JME (lod score 2.5/4.2), a locus on chromosome 8 influencing non-JME forms of IGE (lod score 3.8/2.5), and, more tentatively, two newly discovered loci for absence seizures on chromosome 5 (lod scores 3.8/2.8 and 3.4/1.9). Our data also suggest that the genetic classification of different forms of IGE is likely to cut across the clinical classification of these subforms of IGE. We hypothesize that interactions of different combinations of these loci produce the related heterogeneous phenotypes seen in IGE families.

American journal of human genetics, 1993

The association of some diseases with specific alleles of certain genetic markers has been diffic... more The association of some diseases with specific alleles of certain genetic markers has been difficult to explain. Several explanations have been proposed for the phenomenon of association, e.g. the existence of multiple, interacting genes (epistasis) or a disease locus in linkage disequilibrium with the marker locus. One might suppose that when marker data from families with associated diseases are analyzed for linkage, the existence of the association would assure that linkage will be found, and found at a tight recombination fraction. In fact, however, linkage analyses of some diseases associated with HLA, as well as diseases associated with alleles at other loci located throughout the genome, show significant evidence against linkage, and others show loose linkage, to the puzzlement of many researchers. In part, the puzzlement arises because linkage analysis is ideal for looking for loci that are necessary, even if not sufficient, for disease expression but may be much less useful...

American journal of human genetics, 1984

Cannings and Thompson suggested conditioning on the phenotypes of the probands to correct for asc... more Cannings and Thompson suggested conditioning on the phenotypes of the probands to correct for ascertainment in the analysis of pedigree data. The method assumes single ascertainment and can be expected to yield asymptotically biased parameter estimates except in this specific case. However, because the method is easy to apply, we investigated the degree of bias in the more typical situation of multiple ascertainment, in the hope that the bias might be small and that the method could be applied more generally. To explore the utility of conditioning on probands to correct for multiple ascertainment, we calculated the asymptotic value of the segregation ratio for two versions of the simple Mendelian segregation model on sibship data. For both versions, we found that this asymptotic value decreased approximately linearly as the ascertainment probability increased. When ascertainment was complete, the segregation-ratio estimates were zero, not just asymptotically but for finite sample si...

The HLA data from nine published studies on Type 1 (insulin-dependent) diabetes were examined to ... more The HLA data from nine published studies on Type 1 (insulin-dependent) diabetes were examined to see whether a three-allele model for the inheritance of Type 1 diabetes at the HLA-associated locus could be rejected. None of the data rejected the three-allele model. The data were also examined to see whether they would reject a recessive model. Out of the nine data sets, five rejected a recessive and four did not. The p value for all studies together rejected a recessive. Two of the data sets allowed us to test the hypothesis that multiplex and simplex families would exhibit different modes of inheritance. Multiplex data from both data sets rejected recessive inheritance while the multiplex data from only one data set also rejected three-allele inheritance. The results of assuming a recessive model and analyzing the data from simplex families led to different results from the two data sets. In addition, data from a non-European population were examined and found to reject both recessive and three-allele inheritance for Type 1 diabetes at the HLA-associated locus.

Genetic Epidemiology, 1988

We examined the inheritance of juvenile myoclonic epilepsy (JME). We looked at both the trait of ... more We examined the inheritance of juvenile myoclonic epilepsy (JME). We looked at both the trait of "epilepsy" and the trait of "epilepsy-plus-EEG abnormalities," since EEG abnormalities are frequently found in the clinically unaffected sibs of JME patients. We tested several modes of inheritance including the fully penetrant recessive and several two-locus models. We could reject all models tested (fully penetrant single-locus and two-locus models) when abnormal EEGs were classified as "unaffected." We could also reject the fully penetrant single locus models when family members with abnormal EEGs were considered "affected." We also rejected the two-locus model where the inheritance at both loci was dominant. The two-locus model where both loci showed recessive inheritance could not be rejected, nor could the model where one locus was dominant and the other recessive. Our results suggest that the underlying predisposition for JME is genetically determined and is partially reflected in the abnormal EEGs found in clinically unaffected family members.

Genetic Epidemiology, 1995

Three interval estimation procedures were evaluated to determine the method which provides the mo... more Three interval estimation procedures were evaluated to determine the method which provides the most accurate estimates for the recombination fraction, 8. The lod-0.83 support interval, the jackknife confidence interval, and the confidence interval based on estimated asymptotic standard error were compared by calculating the coverage probabilities of each. Family data that were simulated under the model of a single fully penetrant, dominant disease locus at some distance, 8, from fully informative matings were used. Comparisons were based on 1,000 random samples of size 20, 60, and 100 families. In addition, a methodology for obtaining prediction intervals for 8 was developed. This procedure is of practical use and does not require asymptotic assumptions based on large sample theory. The results provide an a priori idea about precision of the estimates, as well as empirical interval estimates of 8. Graphs of the authors' Monte Carlo intervals are presented for these simulations. Investigators studying different traits, however, could condition specifically on the family structure and distribution of the disease they are investigating and obtain similar graphs.

Genetic Epidemiology, 1996

Marker allele-disease association and linkage between a disease locus and a marker locus are two ... more Marker allele-disease association and linkage between a disease locus and a marker locus are two different phenomena. Linkage without evidence of association and association without evidence of linkage are possible observations. Linkage analysis uses marker loci and the phenomenon of recombination to look for disease-related loci which are presumably major contributors to disease expression ("necessary" loci). However, the phenomenon of association is more complex. One explanation for the existence of an association is that there is a "necessary" locus in linkage disequilibrium with a marker locus. Another explanation is that the marker locus itself (or a closely linked locus in linkage disequilibrium with the marker) is a "susceptibility" locus, which increases the probability of contracting the disease but is not necessary for disease expression. Although there are other possible explanations for the existence of an association, these two can lead to different results when family data from a disease showing association are analyzed for linkage between the associated marker and the disease. If the linkage disequilibrium hypothesis is correct, there will be evidence for linkage. If the susceptibility locus hypothesis is correct, there may be strong evidence against linkage. In this work, we explore a method that could indicate whether an association is due to a susceptibility locus or a necessary locus. We show that, by dividing families based on the presence or absence of the associated marker allele in a randomly chosen affected sib, calculating lod scores, and then calculating a heterogeneity statistic, we could distinguish whether linkage data came from a susceptibility locus or a necessary locus.

Computers in Biology and Medicine, 1985

We report on the design and implementation of a computer facility (called the Data Bank) for medi... more We report on the design and implementation of a computer facility (called the Data Bank) for medical research. The system was designed to be accessible to medical researchers and their staff. Its chief requirements were ability to handle large volumes of data efficiently and be reasonably user-friendly, since most medical research staff members are computer-naive. We describe how we set-up a user friendly system and report on the problems we had in making it accessible. The chief problems were caused by difficult communication between computer staff and medical research staff. We discuss the ways we have attempted to overcome the problems.

Archives of General Psychiatry, 1992

The most popular strategy for finding genes in psychiatric diseases has been to focus on large pe... more The most popular strategy for finding genes in psychiatric diseases has been to focus on large pedigrees with many affected members. While this strategy has sound advantages, it also has drawbacks that have seldom been addressed. The strategy of using smaller families also has its place in a linkage analysis. To illustrate the point, I discuss herein the successful search for a gene for another common complex disease, namely, idiopathic primary generalized epilepsy. There, investigators in the Los Angeles (Calif) Epilepsy Program used mostly nuclear families who were chosen through a proband with highly specific characteristics. An independent study, using a different strategy but one still focused on small families, then confirmed the linkage. However, investigators of both epilepsy projects put much care into determining which clinical characteristics would be used to define the index cases. The implications for the study of psychiatric disease are as follows: (1) careful attention must be paid to clinical presentation, and (2) there is room for both large-pedigree and small-family strategies in designing linkage studies.

Annals of Clinical and Translational Neurology, 2020

Objective: Impulsivity is a multidimensional construct that can predispose to psychopathology. Me... more Objective: Impulsivity is a multidimensional construct that can predispose to psychopathology. Meta-analysis demonstrates an association between response impulsivity and Juvenile Myoclonic Epilepsy (JME), a common genetic generalized epilepsy. Here, we test the hypotheses that trait impulsivity is (i) elevated in JME compared to controls; (ii) moderated by specific seizure characteristics; and (iii) associated with psychiatric adverse effects of antiepileptic drugs (AEDs). Methods: 322 participants with JME and 126 age and gender-matched controls completed the Barratt's Impulsiveness Scale (BIS-brief) alongside information on seizure history and AED use. We compared group BIS-brief scores and assessed associations of JME BIS-brief scores with seizure characteristics and AED adverse effects. Results: The mean BIS-brief score in JME was 18.1 AE 4.4 compared with 16.2 AE 4.1 in controls (P = 0.0007). Elevated impulsivity was associated with male gender (P = 0.027), frequent absence seizures (P = 0.0004) and lack of morning predominance of myoclonus (P = 0.008). High impulsivity significantly increased the odds of a psychiatric adverse event on levetiracetam (P = 0.036), but not any other psychiatric or somatic adverse 138

American journal of human genetics, 1996

American journal of human genetics, 1993

American journal of human genetics, 1982

There appear to be several alleles of the hexosaminidase A (HEX A) gene that lead to different cl... more There appear to be several alleles of the hexosaminidase A (HEX A) gene that lead to different clinical syndromes. In addition to the infantile-onset Tay-Sachs disease (TSD), there is a juvenile-onset and an adult-onset form, which are also characterized by low HEX A levels. There are also apparently healthy adults with low HEX A activity. Based primarily on data from population screening for TSD carrier status, we estimate the allele frequency of the combined variant alleles for which data are available to be about 4.5 x 10(-4) and the frequency of adults showing zero HEX A levels (when tested using artificial substrate) to be about 1:67,000. The implications for population screening and prenatal diagnosis are discussed.

American journal of human genetics, 1986

In many family studies, it is often difficult to know exactly how the families were ascertained. ... more In many family studies, it is often difficult to know exactly how the families were ascertained. Even if known, the circumstances under which the families came to the attention of the study may violate the assumptions of classical ascertainment bias correction. The purpose of this work was to investigate the effect on segregation analysis of violations of the assumptions of the classical ascertainment model. We simulated family data generated under a simple recessive model of inheritance. We then ascertained families under different "scenarios." These scenarios were designed to simulate actual conditions under which families come to the attention of-and then interact with-a clinic or genetic study. We show that how one designates probands, which one must do under the classical ascertainment model, can influence parameter estimation and hypothesis testing. We demonstrate that, in some cases, there may be no "correct" way to designate probands. Further, we show tha...

Proceedings of the National Academy of Sciences, 2008

Hashimoto's thyroiditis (HT) is associated with HLA, but the associated allele is still contr... more Hashimoto's thyroiditis (HT) is associated with HLA, but the associated allele is still controversial. We hypothesized that specific HLA-DR pocket-sequence variants are associated with HT and that similar variants in the murine I-E locus (homologous to HLA-DR) predispose to experimental autoimmune thyroiditis (EAT), a classical mouse model of HT. Therefore, we sequenced the polymorphic exon 2 of the HLA-DR gene in 94 HT patients and 149 controls. In addition, we sequenced exon 2 of the I-E gene in 22 strains of mice, 12 susceptible to EAT and 10 resistant. Using logistic regression analysis, we identified a pocket amino acid signature, Tyr-26, Tyr-30, Gln-70, Lys-71, strongly associated with HT ( P = 6.18 × 10 −5 , OR = 3.73). Lys-71 showed the strongest association ( P = 1.7 × 10 −8 , OR = 2.98). This association was seen across HLA-DR types. The 5-aa haplotype Tyr-26, Tyr-30, Gln-70, Lys-71, Arg-74 also was associated with HT ( P = 3.66 × 10 −4 ). In mice, the I-E pocket amino...

Osteoporosis International, 2007

Animal models suggest a role for osteonectin/SPARC in determination of bone mass. We found haplot... more Animal models suggest a role for osteonectin/SPARC in determination of bone mass. We found haplotypes consisting of three single nucleotide polymorphisms (SNPs) in the 3′ untranslated region (UTR) of the osteonectin gene are associated with bone density in Caucasian men with idiopathic osteoporosis. Introduction-Osteonectin is a matricellular protein regulating matrix assembly, osteoblast differentiation, and survival. Animal studies indicate that osteonectin is essential for normal bone mass. The 3′ UTR is a regulatory region controlling mRNA stability, trafficking, and translation, and we determined whether osteonectin 3′ UTR haplotypes could be associated with bone mass and/or idiopathic osteoporosis. Methods-Single strand conformation polymorphism and allele-specific PCR analysis were used to assess alleles at osteonectin cDNA bases 1046, 1599, and 1970, using genomic DNA from middleaged Caucasian men with idiopathic, low turnover osteoporosis (n=56) and matched controls (n=59). Bone density was measured by DXA at spine, hip and radius. Allele and haplotype frequencies were analyzed by Chi square analysis and Fisher's exact test. Results-Five common osteonectin 3′ UTR haplotypes were identified. The frequency of one haplotype (1046C-1599C-1970T) was higher in controls compared with patients, and this haplotype was also associated with higher bone densities at multiple sites in patients. In contrast, a second haplotype (1046C-1599G-1970T) was associated with lower bone densities in patients at multiple sites. Conclusions-Osteonectin regulates skeletal remodeling and bone mass in animals, and haplotypes in the 3′ UTR of this gene are associated with bone density in Caucasian men with idiopathic osteoporosis.

Journal of Biological Chemistry, 2011

Autoimmune thyroid diseases (AITD) arise from complex interactions between genetic, epigenetic, a... more Autoimmune thyroid diseases (AITD) arise from complex interactions between genetic, epigenetic, and environmental factors. Whole genome linkage scans and association studies have established thyroglobulin (TG) as a major AITD susceptibility gene. However, the causative TG variants and the pathogenic mechanisms are unknown. Here, we describe a genetic/ epigenetic mechanism by which a newly identified TG promoter single-nucleotide polymorphism (SNP) variant predisposes to AITD. Sequencing analyses followed by case control and familybased association studies identified an SNP (؊1623A3 G) that was associated with AITD in the Caucasian population (p ‫؍‬ 0.006). We show that the nucleotide substitution introduced by SNP (؊1623A/G) modified a binding site for interferon regulatory factor-1 (IRF-1), a major interferon-induced transcription factor. Using chromatin immunoprecipitation, we demonstrated that IRF-1 binds to the 5 TG promoter motif, and the transcription factor binding correlates with active chromatin structure and is marked by enrichment of mono-methylated Lys-4 residue of histone H3, a signature of active transcriptional enhancers. Using reporter mutations and siRNA approaches, we demonstrate that the disease-associated allele (G) conferred increased TG promoter activity through IRF-1 binding. Finally, treatment of thyroid cells with interferon ␣, a known trigger of AITD, increased TG promoter activity only when it interacted with the disease-associated variant through IRF-1 binding. These results reveal a new mechanism of interaction between environmental (IFN␣) and genetic (TG) factors to trigger AITD. Autoimmune thyroid diseases (AITD), 4 including Graves disease (GD) and Hashimoto thyroiditis (HT), are character

Human Heredity, 2004

Human recombination fraction (RF) can differ between males and females, but investigators do not ... more Human recombination fraction (RF) can differ between males and females, but investigators do not always know which disease genes are located in genomic areas of large RF sex differences. Knowledge of RF sex differences contributes to our understanding of basic biology and can increase the power of a linkage study, improve gene localization, and provide clues to possible imprinting. One way to detect these differences is to use lod scores. In this study we focused on detecting RF sex differences and answered the following questions, in both phase-known and phase-unknown matings: (1) How large a sample size is needed to detect a RF sex difference? (2) What are ‘optimal’ proportions of paternally vs. maternally informative matings? (3) Does ascertaining nonoptimal proportions of paternally or maternally informative matings lead to ascertainment bias? Our results were as follows: (1) We calculated expected lod scores (ELODs) under two different conditions: ‘unconstrained,’ allowing sex-...

American Journal of Medical Genetics, 1983

One hundred families with insulin-dependent diabetes mellitus (IDDM) were analyzed for linkage wi... more One hundred families with insulin-dependent diabetes mellitus (IDDM) were analyzed for linkage with 27 genetic markers, including HLA, properdin factor B (BF), and glyoxalase 1 (GLO) on chromosome 6, and Kidd blood group (Jk) on chromosome 2. The linkage analyses were performed under several different genetic models. An approximate correction for two-locus linkage analysis was developed and applied to four markers. Two different heterogeneity tests were implemented and applied to all the markers. One, the Predivided-Sample Test, utilizes various criteria thought to be relevant to genetic heterogeneity in IDDM. The other, the Admixture Test, looks for heterogeneity without specifying a priori how the sample should be divided. Results continued to support linkage of IDDM with three chromosome 6 markers: HLA, BF, and GLO. The total lod score for Kidd blood group, under the recessive model with 20% penetrance, is 1.63-down 1.2 from the 2.83 reported by us earlier. The only other marker whose lod score exceeded 1.0 under any model was pancreatic amylase (AMY2). The two-locus correction, which involved lowering the penetrance values used in the analysis, affected estimates of 0 (recombination fraction) but did not markedly change the lod scores themselves. There was little evidence for heterogeneity within any of the lod scores, under either the Predivided-Sample Test or the Admixture Test.

The American Journal of Human Genetics, 2001

Annals of Neurology, 2001

Idiopathic generalized epilepsy (IGE) is a common, complex disease with an almost exclusively gen... more Idiopathic generalized epilepsy (IGE) is a common, complex disease with an almost exclusively genetic etiology but with variable phenotypes. Clinically, IGE can be divided into different syndromes. Varying lines of evidence point to the involvement of several interacting genes in the etiology of IGE. We performed a genome scan in 91 families ascertained through a proband with adolescent-onset IGE. The IGEs included juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), and epilepsy with generalized tonic clonic seizures (EGTCS). Our linkage results support an oligogenic model for IGE, with strong evidence for a locus common to most IGEs on chromosome 18 (lod score 4.4/5.2 multipoint/ two-point) and other loci that may influence specific seizure phenotypes for different IGEs: a previously identified locus on chromosome 6 for JME (lod score 2.5/4.2), a locus on chromosome 8 influencing non-JME forms of IGE (lod score 3.8/2.5), and, more tentatively, two newly discovered loci for absence seizures on chromosome 5 (lod scores 3.8/2.8 and 3.4/1.9). Our data also suggest that the genetic classification of different forms of IGE is likely to cut across the clinical classification of these subforms of IGE. We hypothesize that interactions of different combinations of these loci produce the related heterogeneous phenotypes seen in IGE families.

American journal of human genetics, 1993

The association of some diseases with specific alleles of certain genetic markers has been diffic... more The association of some diseases with specific alleles of certain genetic markers has been difficult to explain. Several explanations have been proposed for the phenomenon of association, e.g. the existence of multiple, interacting genes (epistasis) or a disease locus in linkage disequilibrium with the marker locus. One might suppose that when marker data from families with associated diseases are analyzed for linkage, the existence of the association would assure that linkage will be found, and found at a tight recombination fraction. In fact, however, linkage analyses of some diseases associated with HLA, as well as diseases associated with alleles at other loci located throughout the genome, show significant evidence against linkage, and others show loose linkage, to the puzzlement of many researchers. In part, the puzzlement arises because linkage analysis is ideal for looking for loci that are necessary, even if not sufficient, for disease expression but may be much less useful...

American journal of human genetics, 1984

Cannings and Thompson suggested conditioning on the phenotypes of the probands to correct for asc... more Cannings and Thompson suggested conditioning on the phenotypes of the probands to correct for ascertainment in the analysis of pedigree data. The method assumes single ascertainment and can be expected to yield asymptotically biased parameter estimates except in this specific case. However, because the method is easy to apply, we investigated the degree of bias in the more typical situation of multiple ascertainment, in the hope that the bias might be small and that the method could be applied more generally. To explore the utility of conditioning on probands to correct for multiple ascertainment, we calculated the asymptotic value of the segregation ratio for two versions of the simple Mendelian segregation model on sibship data. For both versions, we found that this asymptotic value decreased approximately linearly as the ascertainment probability increased. When ascertainment was complete, the segregation-ratio estimates were zero, not just asymptotically but for finite sample si...

The HLA data from nine published studies on Type 1 (insulin-dependent) diabetes were examined to ... more The HLA data from nine published studies on Type 1 (insulin-dependent) diabetes were examined to see whether a three-allele model for the inheritance of Type 1 diabetes at the HLA-associated locus could be rejected. None of the data rejected the three-allele model. The data were also examined to see whether they would reject a recessive model. Out of the nine data sets, five rejected a recessive and four did not. The p value for all studies together rejected a recessive. Two of the data sets allowed us to test the hypothesis that multiplex and simplex families would exhibit different modes of inheritance. Multiplex data from both data sets rejected recessive inheritance while the multiplex data from only one data set also rejected three-allele inheritance. The results of assuming a recessive model and analyzing the data from simplex families led to different results from the two data sets. In addition, data from a non-European population were examined and found to reject both recessive and three-allele inheritance for Type 1 diabetes at the HLA-associated locus.

Genetic Epidemiology, 1988

We examined the inheritance of juvenile myoclonic epilepsy (JME). We looked at both the trait of ... more We examined the inheritance of juvenile myoclonic epilepsy (JME). We looked at both the trait of "epilepsy" and the trait of "epilepsy-plus-EEG abnormalities," since EEG abnormalities are frequently found in the clinically unaffected sibs of JME patients. We tested several modes of inheritance including the fully penetrant recessive and several two-locus models. We could reject all models tested (fully penetrant single-locus and two-locus models) when abnormal EEGs were classified as "unaffected." We could also reject the fully penetrant single locus models when family members with abnormal EEGs were considered "affected." We also rejected the two-locus model where the inheritance at both loci was dominant. The two-locus model where both loci showed recessive inheritance could not be rejected, nor could the model where one locus was dominant and the other recessive. Our results suggest that the underlying predisposition for JME is genetically determined and is partially reflected in the abnormal EEGs found in clinically unaffected family members.

Genetic Epidemiology, 1995

Three interval estimation procedures were evaluated to determine the method which provides the mo... more Three interval estimation procedures were evaluated to determine the method which provides the most accurate estimates for the recombination fraction, 8. The lod-0.83 support interval, the jackknife confidence interval, and the confidence interval based on estimated asymptotic standard error were compared by calculating the coverage probabilities of each. Family data that were simulated under the model of a single fully penetrant, dominant disease locus at some distance, 8, from fully informative matings were used. Comparisons were based on 1,000 random samples of size 20, 60, and 100 families. In addition, a methodology for obtaining prediction intervals for 8 was developed. This procedure is of practical use and does not require asymptotic assumptions based on large sample theory. The results provide an a priori idea about precision of the estimates, as well as empirical interval estimates of 8. Graphs of the authors' Monte Carlo intervals are presented for these simulations. Investigators studying different traits, however, could condition specifically on the family structure and distribution of the disease they are investigating and obtain similar graphs.

Genetic Epidemiology, 1996

Marker allele-disease association and linkage between a disease locus and a marker locus are two ... more Marker allele-disease association and linkage between a disease locus and a marker locus are two different phenomena. Linkage without evidence of association and association without evidence of linkage are possible observations. Linkage analysis uses marker loci and the phenomenon of recombination to look for disease-related loci which are presumably major contributors to disease expression ("necessary" loci). However, the phenomenon of association is more complex. One explanation for the existence of an association is that there is a "necessary" locus in linkage disequilibrium with a marker locus. Another explanation is that the marker locus itself (or a closely linked locus in linkage disequilibrium with the marker) is a "susceptibility" locus, which increases the probability of contracting the disease but is not necessary for disease expression. Although there are other possible explanations for the existence of an association, these two can lead to different results when family data from a disease showing association are analyzed for linkage between the associated marker and the disease. If the linkage disequilibrium hypothesis is correct, there will be evidence for linkage. If the susceptibility locus hypothesis is correct, there may be strong evidence against linkage. In this work, we explore a method that could indicate whether an association is due to a susceptibility locus or a necessary locus. We show that, by dividing families based on the presence or absence of the associated marker allele in a randomly chosen affected sib, calculating lod scores, and then calculating a heterogeneity statistic, we could distinguish whether linkage data came from a susceptibility locus or a necessary locus.

Computers in Biology and Medicine, 1985

We report on the design and implementation of a computer facility (called the Data Bank) for medi... more We report on the design and implementation of a computer facility (called the Data Bank) for medical research. The system was designed to be accessible to medical researchers and their staff. Its chief requirements were ability to handle large volumes of data efficiently and be reasonably user-friendly, since most medical research staff members are computer-naive. We describe how we set-up a user friendly system and report on the problems we had in making it accessible. The chief problems were caused by difficult communication between computer staff and medical research staff. We discuss the ways we have attempted to overcome the problems.

Archives of General Psychiatry, 1992

The most popular strategy for finding genes in psychiatric diseases has been to focus on large pe... more The most popular strategy for finding genes in psychiatric diseases has been to focus on large pedigrees with many affected members. While this strategy has sound advantages, it also has drawbacks that have seldom been addressed. The strategy of using smaller families also has its place in a linkage analysis. To illustrate the point, I discuss herein the successful search for a gene for another common complex disease, namely, idiopathic primary generalized epilepsy. There, investigators in the Los Angeles (Calif) Epilepsy Program used mostly nuclear families who were chosen through a proband with highly specific characteristics. An independent study, using a different strategy but one still focused on small families, then confirmed the linkage. However, investigators of both epilepsy projects put much care into determining which clinical characteristics would be used to define the index cases. The implications for the study of psychiatric disease are as follows: (1) careful attention must be paid to clinical presentation, and (2) there is room for both large-pedigree and small-family strategies in designing linkage studies.