Previous Experience and   

Academic Work 

Seth's Bio 

Seth joined IBM in November 2016 with the mission to transform the Cloud and Cognitive Software operations using data and AI,  as well as to share his perspective with IBM clients.

 

Thanks to his extensive experience and very unique background, which ranges from a PhD in genetics to the domain of business operations, Seth is a prominent voice in the data and AI field, and has provided his expertise to several Fortune 500 companies which he helped accelerate the operationalization of the AI practice into the business.

Currently, Seth is leading IBM’s digital transformation by fundamentally changing how IBM’s Cloud and Cognitive Software business is operated. Seth developed a specific methodology centered around surfacing data and implementing and scale AI projects which are strictly tied to the key business objectives of the business., applying AI in consumable and interactive dashboards as well as financial management and scenario planning and simulation. 

Generating value from data

AI is built by leveraging MLOpps to operationalize and industrialize predictive and prescriptive insights. By combining his methodology and technologies Seth is delivering value to the business by leveraging 5 main data assets which can be rallied around the core concepts of  Pipeline360, Salesforce360, Ledger360, Product360 and Client360

His vision of data as shareable enterprise assets, as opposed to the old concept of data ownership, is a key building block of the strategy that Seth has conceived and created to operationalize data science and AI into the enterprise. These ideas and concepts are laid out into a collection of articles around data science and AI which starts by describing how an enterprise can begin growing data science and AI teams.

 

Seth’s leadership in the domain of data and AI crosses many areas of IBM: besides business and clients, Seth is also the chairperson of the IBM Data Science Profession. Seth’s keen attention to the topic of talent development in data science led him to set a very specific objective for the IBM Data Science Profession: the definition of the data scientist role by the creation of standards, certification processes, hiring practices, compensation & benchmarking as well as community development. The board spearheaded the IBM and OpenGroup, Open Certified Data Scientist program. A skills-based assessment and qualification program for data scientists inside IBM as well as externally via the OpenGroup

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 Academic  

Publications 

Research  Studies Genetics  

Academic Publications

Study on essential derivation in maize: III. Selection and evaluation of a panel of single nucleotide polymorphism loci for use in European and North American germplasm

In Crop Science 55 (3), 1170-1180

Abstract: Pairwise distance data for maize (Zea maysL.) inbred lines generated using sets of single  nucleotide polymorphisms (SNPs) selected  from a 50k Infinium array were compared with  pairwise distances generated using a set of 163 simple sequence repeat (SSR) loci previously  identified to help determine essentially derived  variety (EDV) status (UPOV, 1991). Final com-parisons were made using 26,874 SNPs after discarding SNPs with insufficient data quality or vulnerability to ascertainment bias. Inbred lines developed in the United States or in western  Europe that had been previously published to  establish SSR-based thresholds provided the  means to determine equivalent SNP-based pro-tocols. Use of 3072 SNPs selected to provide even genomic coverage according to genetic  and physical maps provided robust, precise,  high discrimination among inbred lines with con-sistent zonal classification with up to 20% miss-ing data. Comparisons of intercepts and slopes for SSR and SNP inbred pairwise distance data translated the 82% SSR green-orange similar-ity threshold to 91% using SNPs and the 90%  SSR orange-red threshold to 95% using SNPs. Information required to conduct analyses using these 3072 SNPS is presented

Quantitative Trait Locus Analysis of Carotid Atherosclerosis in an Intercross Between C57BL/6 and C3H Apolipoprotein E–Deficient Mice

In Stroke 39 (1), 166-173

Abstract: 

Background and Purpose— Inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) exhibit marked differences in atherosclerotic lesion formation in the carotid arteries on the apolipoprotein E–deficient (apoE−/−) background when fed a Western diet. Quantitative trait locus analysis was performed on an intercross between B6.apoE−/− and C3H.apoE−/− mice to determine genetic factors contributing to variation in the phenotype.

Methods— Female B6.apoE−/− mice were crossed with male C3H.apoE−/− mice to generate F1 hybrids, which were intercrossed to generate 241 female F2 progeny. At 6 weeks of age, F2 mice were started on a Western diet. After being fed the diet for 12 weeks, F2 mice were analyzed for phenotypes such as lesion size in the left carotid arteries and plasma lipid levels and typed for 154 genetic markers spanning the mouse genome.

Results— One significant quantitative trait locus, named CAth1 (25 cM, log of the odds score: 4.5), on chromosome 12 and 4 suggestive quantitative trait loci, on chromosomes 1, 5, 6, and 11, respectively, were identified to influence carotid lesion size. One significant quantitative trait locus on distal chromosome 1 accounted for major variations in plasma low-density lipoprotein/very-low-density lipoprotein, high-density lipoprotein cholesterol, and triglyceride levels. Carotid lesion size was not significantly correlated with plasma low-density lipoprotein/very-low-density lipoprotein or high-density lipoprotein cholesterol levels.

Conclusions— These data indicate that the loci for carotid lesions do not overlap with those for aortic lesions as identified in a previous cross derived from the same parental strains, and carotid atherosclerosis and plasma lipids are controlled by separate genetic factors in the B6 and C3H mouse model.

A novel locus for adolescent idiopathic scoliosis on chromosome 12p

In Journal of Orthopaedic Research 27 (10), 1366-1372

Abstract: Adolescent idiopathic scoliosis (AIS) is a common disorder with strong evidence for genetic predisposition. Quantitative trait loci (QTLs) for AIS susceptibility have been identified on chromosomes. We performed a genome‐wide genetic linkage scan in seven multiplex families using 400 marker loci with a mean spacing of 8.6 cM. We used Genehunter Plus to generate linkage statistics, expressed as homogeneity (HLOD) scores, under dominant and recessive genetic models. We found a significant linkage signal on chromosome 12p, whose support interval extends from near 12pter, spanning approximately 10 million bases or 31 cM. Fine mapping within the region using 20 additional markers reveals maximum HLOD = 3.7 at 5 cM under a dominant inheritance model, and a split peak maximum HLOD = 3.2 at 8 and 18 cM under a recessive inheritance model. The linkage support interval contains 95 known genes. We found evidence suggestive of linkage on chromosomes 1, 6, 7, 8, and 14. This study is the first to find evidence of an AIS susceptibility locus on chromosome 12. Detection of AIS susceptibility QTLs on multiple chromosomes in this and other studies demonstrate that the condition is genetically heterogeneous.

Combining gene expression, demographic and clinical data in modeling disease: a case study of bipolar disorder and schizophrenia

In J Struyf, S Dobrin, D PageBmc Genomics 9 (1), 531

Abstract: Background – This paper presents a retrospective statistical study on the newly-released data set by the Stanley Neuropathology Consortium on gene expression in bipolar disorder and schizophrenia. This data set contains gene expression data as well as limited demographic and clinical data for each subject. Previous studies using statistical classification or machine learning algorithms have focused on gene expression data only. The present paper investigates if such techniques can benefit from including demographic and clinical data.

 

Results – We compare six classification algorithms: support vector machines (SVMs), nearest shrunken centroids, decision trees, ensemble of voters, naïve Bayes, and nearest neighbor. SVMs outperform the other algorithms. Using expression data only, they yield an area under the ROC curve of 0.92 for bipolar disorder versus control, and 0.91 for schizophrenia versus control. By including demographic and clinical data, classification performance improves to 0.97 and 0.94 respectively.

Conclusion – This paper demonstrates that SVMs can distinguish bipolar disorder and schizophrenia from normal control at a very high rate. Moreover, it shows that classification performance improves by including demographic and clinical data. We also found that some variables in this data set, such as alcohol and drug use, are strongly associated to the diseases. These variables may affect gene expression and make it more difficult to identify genes that are directly associated to the diseases. Stratification can correct for such variables, but we show that this reduces the power of the statistical methods.

The role of estrogen signaling in schizophrenia

American Journal Of Medical Genetics-A 138 (1)

Quantitative Trait Locus Analysis of Carotid Atherosclerosis in an Intercross Between C57BL/6 and C3H Apolipoprotein E–Deficient Mice

In Stroke 39 (1), 166-173

Abstract: 

Background and Purpose—Inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) exhibit marked differences in atherosclerotic lesion formation in the carotid arteries on the apolipoprotein E– deficient (apoE􏰀/􏰀) background when fed a Western diet. Quantitative trait locus analysis was performed on an intercross between B6.apoE􏰀/􏰀 and C3H.apoE􏰀/􏰀 mice to determine genetic factors contributing to variation in the phenotype.


Methods—Female B6.apoE􏰀/􏰀 mice were crossed with male C3H.apoE􏰀/􏰀 mice to generate F1 hybrids, which were intercrossed to generate 241 female F2 progeny. At 6 weeks of age, F2 mice were started on a Western diet. After being fed the diet for 12 weeks, F2 mice were analyzed for phenotypes such as lesion size in the left carotid arteries and plasma lipid levels and typed for 154 genetic markers spanning the mouse genome.


Results—One significant quantitative trait locus, named CAth1 (25 cM, log of the odds score: 4.5), on chromosome 12 and 4 suggestive quantitative trait loci, on chromosomes 1, 5, 6, and 11, respectively, were identified to influence carotid lesion size. One significant quantitative trait locus on distal chromosome 1 accounted for major variations in plasma low-density lipoprotein/very-low-density lipoprotein, high-density lipoprotein cholesterol, and triglyceride levels. Carotid lesion size was not significantly correlated with plasm
Conclusions—These data indicate that the loci for carotid lesions do not overlap with those for aortic lesions as identified in a previous cross derived from the same parental strains, and carotid atherosclerosis and plasma lipids are controlled by separate genetic factors in the B6 and C3H mouse model.

Identifying potential candidate genes in an Irish bipolar disorder sample linked to 14q21-32.

Ulster Medical Journal . 2008, Vol. 77 Issue 1, p76-76. 1/5p

Abstract: Bipolar affective disorder (BPAD) is a severe and debilitating psychiatric illness. Family, twin and adoption studies have established a substantial genetic component to the illness but the genes involved have yet to be fully elucidated. A 10cM genome-wide linkage scan (WGS) was performed in a collection of 60 Irish BPAD affected sib pairs to locate chromosomal regions that may harbour susceptibility genes. The most significant result was on chromosome 14 at 75cM (14q24). Since the region of the chromosome containing significant P values was substantial, we undertook a fine-mapping analysis to refine the linkage peak. 144 SNP markers (400kb resolution) were analysed in an extended sample of 88 ASPs. Linkage analysis resolved our original linkage peak into 4 separate peaks, two of which overlap with published linkage peaks for related psychiatric disorders, such as anxiety and alcoholism. The most significant NPL score of 2.71 was at 67.84Mb, remarkably close to the original WGS peak score at 68.2Mb. In an additional analysis, two SNPs were found to be associated with BPAD (rs24166076 at 46.97Mb and rs4902942 at 71.21Mb). This project has substantially refined the region of chromosome 14 predicted to contain a candidate susceptibility gene for BPAD

Candidate gene analysis of 21q22: support for S100B as a susceptibility gene for bipolar affective disorder with psychosis

In Am J Med Genet Part B 144B:1094–1096.

Abstract: A genome‐wide scan in 60 bipolar affective disorder (BPAD) affected sib‐pairs (ASPs) identified linkage on chromosome 21 at 21q22 (D21S1446, NPL = 1.42, P = 0.08), a BPAD susceptibility locus supported by multiple studies. Although this linkage only approaches significance, the peak marker is located 12 Kb upstream of S100B, a neurotrophic factor implicated in the pathology of psychiatric disorders, including BPAD and schizophrenia. We hypothesized that the linkage signal at 21q22 may result from pathogenic disease variants within S100B and performed an association analysis of this gene in a collection of 125 BPAD type I trios. S100B single nucleotide polymorphisms (SNPs) rs2839350 (P = 0.022) and rs3788266 (P = 0.031) were significantly associated with BPAD. Since variants within S100B have also been associated with schizophrenia susceptibility, we reanalyzed the data in trios with a history of psychosis, a phenotype in common between the two disorders. SNPs rs2339350 (P = 0.016) and rs3788266 (P = 0.009) were more significantly associated in the psychotic subset. Increased significance was also obtained at the haplotype level. Interestingly, SNP rs3788266 is located within a consensus‐binding site for Six‐family transcription factors suggesting that this variant may directly affect S100B gene expression. Fine‐mapping analyses of 21q22 have previously identified transient receptor potential gene melastatin 2 (TRPM2), which is 2 Mb upstream of S100B, as a possible BPAD susceptibility gene at 21q22. We also performed a family‐based association analysis of TRPM2 which did not reveal any evidence for association of this gene with BPAD. Overall, our findings suggest that variants within the S100B gene predispose to a psychotic subtype of BPAD, possibly via alteration of gene expression. © 2007 Wiley‐Liss, Inc.

Genome‐wide scan of bipolar disorder and investigation of population stratification effects on linkage: Support for susceptibility loci at 4q21, 7q36, 9p21, 12q24, 14q24, and 16p13

In Am J Med Genet Part B 144B:791–801.

Abstract: Bipolar disorder (BPD) is a complex genetic disorder with cycling symptoms of depression and mania. Despite the extreme complexity of this psychiatric disorder, attempts to localize genes which confer vulnerability to the disorder have had some success. Chromosomal regions including 4p16, 12q24, 18p11, 18q22, and 21q21 have been repeatedly linked to BPD in different populations. Here we present the results of a whole genome scan for linkage to BPD in an Irish population. Our most significant result was at 14q24 which yielded a non‐parametric LOD (NPL) score of 3.27 at the D14S588 marker with a nominal P‐value of 0.0006 under a narrow (bipolar type I only) model of affection. We previously reported linkage to 14q22‐24 in a subset of the families tested in this analysis. We also obtained suggestive evidence for linkage at 4q21, 9p21, 12q24, and 16p13, chromosomal regions that have all been previously linked to BPD. Additionally, we report on a novel approach to linkage analysis, STRUCTURE‐Guided Linkage Analysis (SGLA), which is designed to reduce genetic heterogeneity and increase the power to detect linkage. Application of this technique resulted in more highly significant evidence for linkage of BPD to three regions including 16p13, a locus that has been repeatedly linked to numerous psychiatric disorders.

Ancient population structure and migration in Africa inferred from genome-wide genetic markers

In American Journal of Physical Anthropology, 232-232

Abstract: SA Tishkoff, FA Reed, A Froment, MW Smith, SM Williams, SA Omar, MJ Kotze, GS Pretorius, M Ibrahim, O Doumbo, M Thera, C Wambebe, SE Dobrin, JL Weber

Identifying potential candidate genes in an irish bipolar disorder sample linked to 14q21-32

In American Journal of Physical Anthropology, 232-232

Abstract: SA Tishkoff, FA Reed, A Froment, MW Smith, SM Williams, SA Omar, MJ Kotze, GS Pretorius, M Ibrahim, O Doumbo, M Thera, C Wambebe, SE Dobrin, JL Weber

F., Cassidy; C., Zhao; J., Badger; C., Delaney; L., Mooney; S., Roche; P., McKeon; S. E., Dobrin

Ulster Medical Journal . 2008, Vol. 77 Issue 1, p76-76. 1/5p

Identifying potential candidate genes in an irish bipolar disorder sample linked to 14q21-32

In American Journal of Physical Anthropology, 232-232

Abstract: Abstract: Bipolar affective disorder (BPAD) is a severe and debilitating psychiatric illness. Family, twin and adoption studies have established a substantial genetic component to the illness but the genes involved have yet to be fully elucidated. A 10cM genome-wide linkage scan (WGS) was performed in a collection of 60 Irish BPAD affected sib pairs to locate chromosomal regions that may harbour susceptibility genes. The most significant result was on chromosome 14 at 75cM (14q24). Since the region of the chromosome containing significant P values was substantial, we undertook a fine-mapping analysis to refine the linkage peak. 144 SNP markers (400kb resolution) were analysed in an extended sample of 88 ASPs. Linkage analysis resolved our original linkage peak into 4 separate peaks, two of which overlap with published linkage peaks for related psychiatric disorders, such as anxiety and alcoholism. The most significant NPL score of 2.71 was at 67.84Mb, remarkably close to the original WGS peak score at 68.2Mb. In an additional analysis, two SNPs were found to be associated with BPAD (rs24166076 at 46.97Mb and rs4902942 at 71.21Mb). This project has substantially refined the region of chromosome 14 predicted to contain a candidate susceptibility gene for BPAD.

SA Tishkoff, FA Reed, A Froment, MW Smith, SM Williams, SA Omar, MJ Kotze, GS Pretorius, M Ibrahim, O Doumbo, M Thera, C Wambebe, SE Dobrin, JL Weber

Academic Publications

Study on essential derivation in maize: III. Selection and evaluation of a panel of single nucleotide polymorphism loci for use in European and North American germplasm

In Crop Science 55 (3), 1170-1180

Abstract: Pairwise distance data for maize (Zea maysL.) inbred lines generated using sets of single  nucleotide polymorphisms (SNPs) selected  from a 50k Infinium array were compared with  pairwise distances generated using a set of 163 simple sequence repeat (SSR) loci previously  identified to help determine essentially derived  variety (EDV) status (UPOV, 1991). Final com-parisons were made using 26,874 SNPs after discarding SNPs with insufficient data quality or vulnerability to ascertainment bias. Inbred lines developed in the United States or in western  Europe that had been previously published to  establish SSR-based thresholds provided the  means to determine equivalent SNP-based pro-tocols. Use of 3072 SNPs selected to provide even genomic coverage according to genetic  and physical maps provided robust, precise,  high discrimination among inbred lines with con-sistent zonal classification with up to 20% miss-ing data. Comparisons of intercepts and slopes for SSR and SNP inbred pairwise distance data translated the 82% SSR green-orange similar-ity threshold to 91% using SNPs and the 90%  SSR orange-red threshold to 95% using SNPs. Information required to conduct analyses using these 3072 SNPS is presented

Quantitative Trait Locus Analysis of Carotid Atherosclerosis in an Intercross Between C57BL/6 and C3H Apolipoprotein E–Deficient Mice

In Stroke 39 (1), 166-173

Abstract: 

Background and Purpose— Inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) exhibit marked differences in atherosclerotic lesion formation in the carotid arteries on the apolipoprotein E–deficient (apoE−/−) background when fed a Western diet. Quantitative trait locus analysis was performed on an intercross between B6.apoE−/− and C3H.apoE−/− mice to determine genetic factors contributing to variation in the phenotype.

Methods— Female B6.apoE−/− mice were crossed with male C3H.apoE−/− mice to generate F1 hybrids, which were intercrossed to generate 241 female F2 progeny. At 6 weeks of age, F2 mice were started on a Western diet. After being fed the diet for 12 weeks, F2 mice were analyzed for phenotypes such as lesion size in the left carotid arteries and plasma lipid levels and typed for 154 genetic markers spanning the mouse genome.

Results— One significant quantitative trait locus, named CAth1 (25 cM, log of the odds score: 4.5), on chromosome 12 and 4 suggestive quantitative trait loci, on chromosomes 1, 5, 6, and 11, respectively, were identified to influence carotid lesion size. One significant quantitative trait locus on distal chromosome 1 accounted for major variations in plasma low-density lipoprotein/very-low-density lipoprotein, high-density lipoprotein cholesterol, and triglyceride levels. Carotid lesion size was not significantly correlated with plasma low-density lipoprotein/very-low-density lipoprotein or high-density lipoprotein cholesterol levels.

Conclusions— These data indicate that the loci for carotid lesions do not overlap with those for aortic lesions as identified in a previous cross derived from the same parental strains, and carotid atherosclerosis and plasma lipids are controlled by separate genetic factors in the B6 and C3H mouse model.

A novel locus for adolescent idiopathic scoliosis on chromosome 12p

In Journal of Orthopaedic Research 27 (10), 1366-1372

Abstract: Adolescent idiopathic scoliosis (AIS) is a common disorder with strong evidence for genetic predisposition. Quantitative trait loci (QTLs) for AIS susceptibility have been identified on chromosomes. We performed a genome‐wide genetic linkage scan in seven multiplex families using 400 marker loci with a mean spacing of 8.6 cM. We used Genehunter Plus to generate linkage statistics, expressed as homogeneity (HLOD) scores, under dominant and recessive genetic models. We found a significant linkage signal on chromosome 12p, whose support interval extends from near 12pter, spanning approximately 10 million bases or 31 cM. Fine mapping within the region using 20 additional markers reveals maximum HLOD = 3.7 at 5 cM under a dominant inheritance model, and a split peak maximum HLOD = 3.2 at 8 and 18 cM under a recessive inheritance model. The linkage support interval contains 95 known genes. We found evidence suggestive of linkage on chromosomes 1, 6, 7, 8, and 14. This study is the first to find evidence of an AIS susceptibility locus on chromosome 12. Detection of AIS susceptibility QTLs on multiple chromosomes in this and other studies demonstrate that the condition is genetically heterogeneous.

Combining gene expression, demographic and clinical data in modeling disease: a case study of bipolar disorder and schizophrenia

In J Struyf, S Dobrin, D PageBmc Genomics 9 (1), 531

Abstract: Background – This paper presents a retrospective statistical study on the newly-released data set by the Stanley Neuropathology Consortium on gene expression in bipolar disorder and schizophrenia. This data set contains gene expression data as well as limited demographic and clinical data for each subject. Previous studies using statistical classification or machine learning algorithms have focused on gene expression data only. The present paper investigates if such techniques can benefit from including demographic and clinical data.

 

Results – We compare six classification algorithms: support vector machines (SVMs), nearest shrunken centroids, decision trees, ensemble of voters, naïve Bayes, and nearest neighbor. SVMs outperform the other algorithms. Using expression data only, they yield an area under the ROC curve of 0.92 for bipolar disorder versus control, and 0.91 for schizophrenia versus control. By including demographic and clinical data, classification performance improves to 0.97 and 0.94 respectively.

Conclusion – This paper demonstrates that SVMs can distinguish bipolar disorder and schizophrenia from normal control at a very high rate. Moreover, it shows that classification performance improves by including demographic and clinical data. We also found that some variables in this data set, such as alcohol and drug use, are strongly associated to the diseases. These variables may affect gene expression and make it more difficult to identify genes that are directly associated to the diseases. Stratification can correct for such variables, but we show that this reduces the power of the statistical methods.

The role of estrogen signaling in schizophrenia

American Journal Of Medical Genetics-A 138 (1)

Quantitative Trait Locus Analysis of Carotid Atherosclerosis in an Intercross Between C57BL/6 and C3H Apolipoprotein E–Deficient Mice

In Stroke 39 (1), 166-173

Abstract: 

Background and Purpose—Inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) exhibit marked differences in atherosclerotic lesion formation in the carotid arteries on the apolipoprotein E– deficient (apoE􏰀/􏰀) background when fed a Western diet. Quantitative trait locus analysis was performed on an intercross between B6.apoE􏰀/􏰀 and C3H.apoE􏰀/􏰀 mice to determine genetic factors contributing to variation in the phenotype.


Methods—Female B6.apoE􏰀/􏰀 mice were crossed with male C3H.apoE􏰀/􏰀 mice to generate F1 hybrids, which were intercrossed to generate 241 female F2 progeny. At 6 weeks of age, F2 mice were started on a Western diet. After being fed the diet for 12 weeks, F2 mice were analyzed for phenotypes such as lesion size in the left carotid arteries and plasma lipid levels and typed for 154 genetic markers spanning the mouse genome.


Results—One significant quantitative trait locus, named CAth1 (25 cM, log of the odds score: 4.5), on chromosome 12 and 4 suggestive quantitative trait loci, on chromosomes 1, 5, 6, and 11, respectively, were identified to influence carotid lesion size. One significant quantitative trait locus on distal chromosome 1 accounted for major variations in plasma low-density lipoprotein/very-low-density lipoprotein, high-density lipoprotein cholesterol, and triglyceride levels. Carotid lesion size was not significantly correlated with plasm
Conclusions—These data indicate that the loci for carotid lesions do not overlap with those for aortic lesions as identified in a previous cross derived from the same parental strains, and carotid atherosclerosis and plasma lipids are controlled by separate genetic factors in the B6 and C3H mouse model.

Identifying potential candidate genes in an Irish bipolar disorder sample linked to 14q21-32.

Ulster Medical Journal . 2008, Vol. 77 Issue 1, p76-76. 1/5p

Abstract: Bipolar affective disorder (BPAD) is a severe and debilitating psychiatric illness. Family, twin and adoption studies have established a substantial genetic component to the illness but the genes involved have yet to be fully elucidated. A 10cM genome-wide linkage scan (WGS) was performed in a collection of 60 Irish BPAD affected sib pairs to locate chromosomal regions that may harbour susceptibility genes. The most significant result was on chromosome 14 at 75cM (14q24). Since the region of the chromosome containing significant P values was substantial, we undertook a fine-mapping analysis to refine the linkage peak. 144 SNP markers (400kb resolution) were analysed in an extended sample of 88 ASPs. Linkage analysis resolved our original linkage peak into 4 separate peaks, two of which overlap with published linkage peaks for related psychiatric disorders, such as anxiety and alcoholism. The most significant NPL score of 2.71 was at 67.84Mb, remarkably close to the original WGS peak score at 68.2Mb. In an additional analysis, two SNPs were found to be associated with BPAD (rs24166076 at 46.97Mb and rs4902942 at 71.21Mb). This project has substantially refined the region of chromosome 14 predicted to contain a candidate susceptibility gene for BPAD

Candidate gene analysis of 21q22: support for S100B as a susceptibility gene for bipolar affective disorder with psychosis

In Am J Med Genet Part B 144B:1094–1096.

Abstract: A genome‐wide scan in 60 bipolar affective disorder (BPAD) affected sib‐pairs (ASPs) identified linkage on chromosome 21 at 21q22 (D21S1446, NPL = 1.42, P = 0.08), a BPAD susceptibility locus supported by multiple studies. Although this linkage only approaches significance, the peak marker is located 12 Kb upstream of S100B, a neurotrophic factor implicated in the pathology of psychiatric disorders, including BPAD and schizophrenia. We hypothesized that the linkage signal at 21q22 may result from pathogenic disease variants within S100B and performed an association analysis of this gene in a collection of 125 BPAD type I trios. S100B single nucleotide polymorphisms (SNPs) rs2839350 (P = 0.022) and rs3788266 (P = 0.031) were significantly associated with BPAD. Since variants within S100B have also been associated with schizophrenia susceptibility, we reanalyzed the data in trios with a history of psychosis, a phenotype in common between the two disorders. SNPs rs2339350 (P = 0.016) and rs3788266 (P = 0.009) were more significantly associated in the psychotic subset. Increased significance was also obtained at the haplotype level. Interestingly, SNP rs3788266 is located within a consensus‐binding site for Six‐family transcription factors suggesting that this variant may directly affect S100B gene expression. Fine‐mapping analyses of 21q22 have previously identified transient receptor potential gene melastatin 2 (TRPM2), which is 2 Mb upstream of S100B, as a possible BPAD susceptibility gene at 21q22. We also performed a family‐based association analysis of TRPM2 which did not reveal any evidence for association of this gene with BPAD. Overall, our findings suggest that variants within the S100B gene predispose to a psychotic subtype of BPAD, possibly via alteration of gene expression. © 2007 Wiley‐Liss, Inc.

Genome‐wide scan of bipolar disorder and investigation of population stratification effects on linkage: Support for susceptibility loci at 4q21, 7q36, 9p21, 12q24, 14q24, and 16p13

In Am J Med Genet Part B 144B:791–801.

Abstract: Bipolar disorder (BPD) is a complex genetic disorder with cycling symptoms of depression and mania. Despite the extreme complexity of this psychiatric disorder, attempts to localize genes which confer vulnerability to the disorder have had some success. Chromosomal regions including 4p16, 12q24, 18p11, 18q22, and 21q21 have been repeatedly linked to BPD in different populations. Here we present the results of a whole genome scan for linkage to BPD in an Irish population. Our most significant result was at 14q24 which yielded a non‐parametric LOD (NPL) score of 3.27 at the D14S588 marker with a nominal P‐value of 0.0006 under a narrow (bipolar type I only) model of affection. We previously reported linkage to 14q22‐24 in a subset of the families tested in this analysis. We also obtained suggestive evidence for linkage at 4q21, 9p21, 12q24, and 16p13, chromosomal regions that have all been previously linked to BPD. Additionally, we report on a novel approach to linkage analysis, STRUCTURE‐Guided Linkage Analysis (SGLA), which is designed to reduce genetic heterogeneity and increase the power to detect linkage. Application of this technique resulted in more highly significant evidence for linkage of BPD to three regions including 16p13, a locus that has been repeatedly linked to numerous psychiatric disorders.

Ancient population structure and migration in Africa inferred from genome-wide genetic markers

In American Journal of Physical Anthropology, 232-232

Abstract: SA Tishkoff, FA Reed, A Froment, MW Smith, SM Williams, SA Omar, MJ Kotze, GS Pretorius, M Ibrahim, O Doumbo, M Thera, C Wambebe, SE Dobrin, JL Weber

SA Tishkoff, FA Reed, A Froment, MW Smith, SM Williams, SA Omar, MJ Kotze, GS Pretorius, M Ibrahim, O Doumbo, M Thera, C Wambebe, SE Dobrin, JL Weber

Investigation of susceptibility loci for bipolar affective disorder on chromosome 21

In AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS 141 

Siobhan Roche, Fiona Cassidy, Chengfeng Zhao, Badger Jonathon, Lisa Mooney, Catherine Delaney, Seth Dobrin, Patrick McKeon

Automating microsatellite genotyping with array tape

In JALA: Journal of the Association for Laboratory Automation 11 (4), 260-267

Abstract: Our laboratory has been testing ways to reduce costs, sample volumes, and decrease labor in microsatellite (or short tandem repeat polymorphism) genotyping. Microsatellite genotyping involves polymerase chain reaction amplification of a short (100–400 bp) fragment of chromosomal DNA that encompasses the tandem repeats followed by electrophoresis to size the amplification products. Using a continuous polypropylene tape (array tape) embossed with 384-well arrays, conforming to the microtiter plate standard, we have been able to perform the amplification reactions in smaller volumes and to decrease handling of stacks of microtiter plates. Instruments were constructed in-house to achieve these results. However, the problem of removal of the samples from the tape for electrophoresis remained. We report here efficient piercing of the tape seal for extraction of the samples using a CO2 laser. Scoring of the seals with the laser weakens it sufficiently to permit extraction of the samples with a syringe array. CO2 lasers are robust systems that do not contain a lot of frequently replaced parts, and do not require frequent recalibration. In addition, the laser is software controlled allowing for highly reproducible scoring and easily switching between 384-, 1536-, and 96-well formats.

Clinical applications of whole-genome association studies: future applications at the bedside

Expert review of molecular diagnostics 6 (4), 551-565

Abstract: Abstract: Until now, performing whole-genome association studies has been an unattainable, but highly desirable, goal for geneticists. With the recent advent of high-throughput genotyping platforms, this goal is now a reality for geneticists today and for clinicians in the not-so-distant future. This review will cover a broad range of topics to provide an overview of this emerging branch of genetics, and will provide references to more specific sources. Specifically, this review will cover the technologies available today and in the near future, the specific types of whole-genome association studies, the benefits and limitations of these studies, the applications to complex disease–gene interactions, diagnostic devices, therapeutics, and finally, we will describe the 5-year perspective and key issues.

Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2

Expert review of molecular diagnostics 6 (4), 551-565

Abstract: Most epileptic disorders can be traced to an abnormality of cortical architecture, channel-mediated currents, neuronal growth and differentiation, or cerebral metabolism.1,2 In most cases, however, the underlying biologic complexity of epilepsy precludes the identification of the genetic cause, and 65 to 79 percent of recurrent seizure syndromes remain unexplained.3 Microarray analysis of DNA samples can be a powerful tool for revealing a genetic lesion in well-defined families. We have used this approach in Old Order Amish families, some members of which have a clinical and neuropathological phenotype that we designate as the cortical dysplasia–focal epilepsy (CDFE) syndrome. We identified a genetic variation in the gene encoding CASPR2 in affected patients, a finding that suggests that CASPR2 influences brain development.

The mania and the delusions surrounding the genomic overlap of bipolar type I and schizophrenia

S Dobrin, P Stafford, C Zhao, SCHIZOPHRENIA RESEARCH 81, 45-46

Kevin A. Strauss, M.D., Erik G. Puffenberger, Ph.D., Matthew J. Huentelman, Ph.D., Steven Gottlieb, M.D., Seth E. Dobrin, Ph.D., Jennifer M. Parod, B.S., Dietrich A. Stephan, Ph.D., and D. Holmes Morton, M.D.

New England Journal of Medicine 354 (13), 1370-1377