American Pedigrees Research Articles

Deciphering the genetic architecture and ethnographic distribution of IRD in three ethnic populations by whole genome sequence analysis.

Patients with inherited retinal dystrophies (IRDs) were recruited from two understudied populations: Mexico and Pakistan as well as a third well-studied population of European Americans to define the genetic architecture of IRD by performing whole-genome sequencing (WGS). Whole-genome analysis was performed on 409 individuals from 108 unrelated pedigrees with IRDs. All patients underwent an ophthalmic evaluation to establish the retinal phenotype. Although the 108 pedigrees in this study had previously been examined for mutations in known IRD genes using a wide range of methodologies including targeted gene(s) or mutation(s) screening, linkage analysis and exome sequencing, the gene mutations responsible for IRD in these 108 pedigrees were not determined. WGS was performed on these pedigrees using Illumina X10 at a minimum of 30X depth. The sequence reads were mapped against hg19 followed by variant calling using GATK. The genome variants were annotated using SnpEff, PolyPhen2, and CADD score; the structural variants (SVs) were called using GenomeSTRiP and LUMPY. We identified potential causative sequence alterations in 61 pedigrees (57%), including 39 novel and 54 reported variants in IRD genes. For 57 of these pedigrees the observed genotype was consistent with the initial clinical diagnosis, the remaining 4 had the clinical diagnosis reclassified based on our findings. In seven pedigrees (12%) we observed atypical causal variants, i.e. unexpected genotype(s), including 4 pedigrees with causal variants in more than one IRD gene within all affected family members, one pedigree with intrafamilial genetic heterogeneity (different affected family members carrying causal variants in different IRD genes), one pedigree carrying a dominant causative variant present in pseudo-recessive form due to consanguinity and one pedigree with a de-novo variant in the affected family member. Combined atypical and large structural variants contributed to about 20% of cases. Among the novel mutations, 75% were detected in Mexican and 50% found in European American pedigrees and have not been reported in any other population while only 20% were detected in Pakistani pedigrees and were not previously reported. The remaining novel IRD causative variants were listed in gnomAD but were found to be very rare and population specific. Mutations in known IRD associated genes contributed to pathology in 63% Mexican, 60% Pakistani and 45% European American pedigrees analyzed. Overall, contribution of known IRD gene variants to disease pathology in these three populations was similar to that observed in other populations worldwide. This study revealed a spectrum of mutations contributing to IRD in three populations, identified a large proportion of novel potentially causative variants that are specific to the corresponding population or not reported in gnomAD and shed light on the genetic architecture of IRD in these diverse global populations.

At the Starting Post: Racing Venues and the Origins of Thoroughbred Racing in Kentucky, 1783–1865

At the Starting Post:Racing Venues and the Origins of Thoroughbred Racing in Kentucky, 1783–1865 Gary A. O'Dell (bio) The citizens of Kentucky, and of the Bluegrass region in particular, have been famously preoccupied with racing spirited horses since the pioneer era, when communities were little more than huddles of primitive cabins in the wilderness and competitions were impulsive sprints through muddy streets still dotted with occasional tree stumps. The first equines brought into Kentucky by the pioneers were all, by necessity, working horses required for taming a wilderness and the needs of a burgeoning agricultural society, but even these common sorts were pitted against one another in races. Among the settlers, however, were men of wealth and a sporting disposition who soon began to import Thoroughbreds from the east, horses described as "hot-blooded" and bred strictly for speed on the racecourse.1 Horseracing was the first spectator sport in America, and by 1800, nearly every significant community in the Bluegrass had established a racecourse of its own, much like present-day small towns erect and support high school football stadiums. Most of these early competitions were "flat" races, in which horses competed on a level racecourse over a predetermined distance, controlled by jockeys mounted on their backs. Most, but not all, flat [End Page 29] racing involved Thoroughbred horses. The sport is comprised of three interrelated components: Thoroughbred horses; the breeders, trainers, jockeys, and other ancillary personnel; and the supporting infrastructure, including the horse farms, racing associations (jockey clubs), and racecourses. Many of the historical accounts of Thoroughbred racing are little more than hagiographies of prominent horses and horsemen of the nineteenth century, focusing upon such celebrated equine heroes as Grey Eagle and Lexington and turf magnates such as Elisha Warfield and Robert Aitcheson Alexander and their lavish Bluegrass estates.2 Recent scholarship, particularly contributions by Maryjean Wall, Katherine Mooney, and James C. Nicholson, has provided more critical examinations of the development and growth of the sport.3 Kentucky's early racing infrastructure has received less attention in the histories; even the best usually contains little more than a brief reference to early quarter-horse racing, the founding of the Kentucky Jockey Club in 1797 and the Kentucky Association in 1826, and then skips to the establishment of Churchill Downs in 1875—as if little of significance had occurred during the intervening half century or in any location other than Lexington or Louisville. By examining primary sources such as advertisements for race meetings in early newspapers and race results published in sporting journals, along with secondary sources, it is possible to reconstruct the hitherto overlooked developmental chronology and geographic distribution of venues for racing in Kentucky prior to the Civil War and to examine the periodic decline and resurgence of the sport during the period. Although turfmen in Lexington—and to a lesser extent Louisville—developed [End Page 30] a stable racing organization and infrastructure in the decades prior to the Civil War, most other communities in the state struggled to maintain such organizations and racing venues. The numerous small tracks and county associations that often existed for only five to ten years at a time show that alongside the story of long-term professionalization and success in building a horse industry in Kentucky, there is a larger story of false starts and failure in the decades before the Civil War. Early Racing Venues in the Bluegrass Region At the time of Kentucky's settlement, the Thoroughbred horse was a relatively recent innovation in the equine world. This fast-paced, high-spirited breed had been developed in England during the seventeenth and eighteenth centuries by crossing native mares with so-called Oriental stallions—Arabian, Barb, and Turkmen horses imported from the Middle East. The importation of British Thoroughbreds to North America was interrupted during the Revolutionary period, although many blood horses brought over by English officers were captured and subsequently became part of American pedigrees. Conversely, the British confiscated American horses for use as military load haulers and cavalry mounts, and often spitefully destroyed some of the finest breeding stock. The disruption of equine livestock and infrastructure was particularly severe in Virginia, essentially bringing the sport...

Pedigree comparison highlights genetic similarities and potential industrial values of sugarcane cultivars

Cultivar pedigrees from two sugarcane origins, 9 Argentine (AR) and 7 American (AM) have been reconstructed, and their genetic similarities (based on coefficient of parentage, COP, estimates) show an average of 0.206 ± 0.054. CP clones that enter the pedigrees of AM cultivars are parents or grandparents of AR cultivars, demonstrating that these genotypes have a strong genetic lineage in common. On average, AR pedigrees are smaller and contain less number of founding species than AM pedigrees. However, the lower height of the former is not explained by the different participation of founding species in the pedigrees. The presence of founding species in AR and AM pedigrees increases with the year of cultivar selection, indicating that more founding species entered the pedigree in recently selected cultivars than in older ones. The ancestry of the 16 cultivars trace back to 3 founding species: Saccharum officinarum, S. barberi, and S. spontaneum, with S. officinarum showing the greatest percentage of participation. As S. sinensis participates in 13 pedigrees and S. robustum in 3, the 5 founding species are present in 2 out of 16 pedigrees. Interestingly, the genus Sorghum enters the pedigree of LCP 85-384 pedigree. Industrial parameters assayed indicate that AR and AM cultivars were preferentially selected for their relatively high sucrose content and sugar yield in accordance with two facts: (i) the genetic background and the sucrose genes of sugarcane hybrids provided by the 68% of participation S. officinarum clones, and (ii) no clones of high fiber S. spontaneum have entered the pedigrees in earlier generations.

Assessing transmission ratio distortion in extended families: a comparison of analysis methods.

A statistical departure from Mendel’s law of segregation is known as transmission ratio distortion. Although well documented in many other organisms, the extent of transmission ratio distortion and its influence in the human genome remains incomplete. Using Genetic Analysis Workshop 19 whole genome sequence data from 20 large Mexican American pedigrees, our goal was to identify potentially distorted regions in the genome using family-based association methods such as the transmission disequilibrium test, the pedigree disequilibrium test, and the family-based association test. Preliminary results showed an unusually high number of transmission ratio distortion signals identified by the transmission disequilibrium test, but this phenomenon could not be replicated by the pedigree disequilibrium test or family-based association test. Applying these tests to different subsets of the data, we found the transmission disequilibrium test to be very sensitive to imputed genotypes. Regression analysis of transmission ratio distortion test p values controlling for minor allele frequency and quality control checks showed that Hardy Weinberg p values are associated with this inflation. Although the transmission disequilibrium test appears confounded by imputation of single nucleotide polymorphisms, the pedigree disequilibrium test and family-based association test seem to offer more robust alternatives when searching for transmission ratio distortion loci in whole genome sequence data from extended families.

Factors associated with heterogeneity in microarray gene expression in peripheral blood mononuclear cells from large pedigrees.

BackgroundGenome-wide microarray expression is a rich source of functional genomic data. We examined evidence for differences in expression from peripheral blood mononuclear cells between individuals, examined some of factors that may be responsible and provide recommendations for analysis.MethodsA total of 643 individuals from 17 large Mexican American pedigrees had microarray gene expression data generated from peripheral blood mononuclear cells. This data has previously been used to map cis- and trans-expression quantitative trait loci using genome-wide linkage analysis. We estimated both principal components and cell proportions in these data, and tested them for association with clinical factors to provide insight into causes of variation in gene expression between individuals.ResultsWe identified that there were highly significant differences in the second principal component of gene expression between pedigrees, with 3 pedigrees being outliers. The estimated cell proportions identified 1 individual who was a gross outlier, as well as pedigrees that differed from others in their estimated proportions of helper and cytotoxic T cells.ConclusionsThese phenomena could be from either pedigree-specific genetic variation, technical artefacts, or clinical factors. Incorporating factors that influence gene expression into genetic analysis, and exclusion of outliers could improve the power of genetic mapping of expression traits.

Constrained multivariate association with longitudinal phenotypes.

BackgroundThe incorporation of longitudinal data into genetic epidemiological studies has the potential to provide valuable information regarding the effect of time on complex disease etiology. Yet, the majority of research focuses on variables collected from a single time point. This aim of this study was to test for main effects on a quantitative trait across time points using a constrained maximum-likelihood measured genotype approach. This method simultaneously accounts for all repeat measurements of a phenotype in families. We applied this method to systolic blood pressure (SBP) measurements from three time points using the Genetic Analysis Workshop 19 (GAW19) whole-genome sequence family simulated data set and 200 simulated replicates. Data consisted of 849 individuals from 20 extended Mexican American pedigrees. Comparisons were made among 3 statistical approaches: (a) constrained, where the effect of a variant or gene region on the mean trait value was constrained to be equal across all measurements; (b) unconstrained, where the variant or gene region effect was estimated separately for each time point; and (c) the average SBP measurement from three time points. These approaches were run for nine genetic variants with known effect sizes (>0.001) for SBP variability and a known gene-centric kernel (MAP4)-based test under the GAW19 simulation model across 200 replicates.ResultsWhen compared to results using two time points, the constrained method utilizing all 3 time points increased power to detect association. Averaging SBP was equally effective when the variant has a large effect on the phenotype, but less powerful for variants with lower effect sizes. However, averaging SBP was far more effective than either the constrained or unconstrained approaches when using a gene-centric kernel-based test.ConclusionWe determined that this constrained multivariate approach improves genetic signal over the bivariate method. However, this method is still only effective in those variants that explain a moderate to large proportion of the phenotypic variance but is not as effective for gene-centric tests.

Exome Sequence Data From Multigenerational Families Implicate AMPA Receptor Trafficking in Neurocognitive Impairment and Schizophrenia Risk

Schizophrenia is a mental disorder characterized by impairments in behavior, thought, and neurocognitive performance. We searched for susceptibility loci at a quantitative trait locus (QTL) previously reported for abstraction and mental flexibility (ABF), a cognitive function often compromised in schizophrenia patients and their unaffected relatives. Exome sequences were determined for 134 samples in 8 European American families from the original linkage study, including 25 individuals with schizophrenia or schizoaffective disorder. At chromosome 5q32-35.3, we analyzed 407 protein-altering variants for association with ABF and schizophrenia status. For replication, significant, Bonferroni-corrected findings were tested against cognitive traits in Mexican American families (n = 959), as well as interrogated for schizophrenia risk using GWAS results from the Psychiatric Genomics Consortium (PGC). From the gene SYNPO, rs6579797 (MAF = 0.032) shows significant associations with ABF (P = .015) and schizophrenia (P = .040), as well as jointly (P = .0027). In the Mexican American pedigrees, rs6579797 exhibits significant associations with IQ (P = .011), indicating more global effects on neurocognition. From the PGC results, other SYNPO variants were identified with near significant effects on schizophrenia risk, with a local linkage disequilibrium block displaying signatures of positive selection. A second missense variant within the QTL, rs17551608 (MAF = 0.19) in the gene WWC1, also displays a significant effect on schizophrenia in our exome sequences (P = .038). Remarkably, the protein products of SYNPO and WWC1 are interaction partners involved in AMPA receptor trafficking, a brain process implicated in synaptic plasticity. Our study reveals variants in these genes with significant effects on neurocognition and schizophrenia risk, identifying a potential pathogenic mechanism for schizophrenia spectrum disorders.

Abstract B12: Recruitment of African American breast cancer pedigrees for The Jewels in Our Genes Study: Recruitment outcomes and sample characteristics

Abstract Background. Few studies have investigated the contribution of inherited genetic variation to breast cancer disparities and fewer have examined whether risk alleles shared in families may contribute to higher risk of aggressive tumors. One barrier is the challenge of effectively recruiting African American families for research. Methods. Using a community-based participatory research (CBPR) orientation, we utilized multi-level methods in an iterative fashion to recruit for a breast cancer genetic linkage study. We recruited affected relative pairs as well as discordant sibling pairs where possible. We analyzed our recruitment yield by method and calculated descriptive statistics for several demographic and clinical characteristics of families selected for genotyping, which includes 281 individuals from 106 pedigrees (197 affecteds, 84 unaffecteds). Results. We recruited 341 African American women (247 with breast cancer and 94 unaffecteds) from 127 families. The top three yields were obtained via collaboration with the Love Army of Women (34% of sample), The National Witness Project (NWP, 29% of sample), and previous epidemiologic studies (24% of sample). Within the set of 106 pedigrees selected for genotyping, 27 pedigrees have one affected relative, 68 pedigrees have 2 affecteds, 10 pedigrees have 3 affecteds, and one pedigree has 6 affecteds. Where adjudicated (n=141, 72%), the mean and median age at diagnosis was 51.6 years (SD 12.0) and 51.6 years, respectively. Affected women were younger at menarche (p=0.002) and more likely to be hysterectomized (p=0.018) compared to unaffected women. According to tumor receptor status, approximately 26% of cases are ER negative, 40% are PR negative, 49% are HER2 negative, and overall 16% are ER/PR/HER2 negative. Conclusions. Approaching recruitment of African American pedigrees with use of a multi-pronged approach that includes collaboration from the community can greatly facilitate success. While our sample has a slightly younger age of onset compared to African American cases in the general population (SEER median age for African Americans is 58 yrs), the sample approximates the US proportion of all invasive breast cancers in the US with regard to triple negative status (∼15%). Citation Format: Youjin Wang, Deborah O. Erwin, Lina Jandorf, Detric Johnson, Veronica Meadows-Ray, Mattye Willis, Heather Ochs-Balcom. Recruitment of African American breast cancer pedigrees for The Jewels in Our Genes Study: Recruitment outcomes and sample characteristics. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B12. doi:10.1158/1538-7755.DISP13-B12

Drinking from the Holy Grail: analysis of whole-genome sequencing from the Genetic Analysis Workshop 18.

The Genetic Analysis Workshops distribute real and simulated human genetic data to allow the development and comparison of methods to detect genetic variants and genes related to biological traits; the results are then presented and discussed at a biennial meeting. The data made available for Genetic Analysis Workshop 18 (GAW18) included whole-genome sequence data for odd-numbered autosomes from 20 large Mexican American pedigrees selected through probands with type 2 diabetes. Real and simulated blood pressure phenotype data were provided to allow the comparison of methods to detect variants and genes associated with blood pressure. Some of the complexity present in the data includes related individuals, repeated quantitative trait outcomes, covariates, medication effects, pharmacokinetic effects, missing data, admixed population, and imputed genotypes. A wide range of analytic approaches were applied to the data. Contributions that focused only on a subset of up to 155 unrelated subjects from the pedigrees were faced with low power. One recommendation for future analysis is the use of the provided null phenotype to allow comparison of type I error across methods. Collaboration between statistical geneticists and molecular biologists or bioinformaticians would provide helpful input to place variants in genes for gene-based association tests.

Applications of machine learning and data mining methods to detect associations of rare and common variants with complex traits.

Machine learning methods (MLMs), designed to develop models using high-dimensional predictors, have been used to analyze genome-wide genetic and genomic data to predict risks for complex traits. We summarize the results from six contributions to our Genetic Analysis Workshop 18 working group; these investigators applied MLMs and data mining to analyses of rare and common genetic variants measured in pedigrees. To develop risk profiles, group members analyzed blood pressure traits along with single-nucleotide polymorphisms and rare variant genotypes derived from sequence and imputation analyses in large Mexican American pedigrees. Supervised MLMs included penalized regression with varying penalties, support vector machines, and permanental classification. Unsupervised MLMs included sparse principal components analysis and sparse graphical models. Entropy-based components analyses were also used to mine these data. None of the investigators fully capitalized on the genetic information provided by the complete pedigrees. Their approaches either corrected for the nonindependence of the individuals within the pedigrees or analyzed only those who were independent. Some methods allowed for covariate adjustment, whereas others did not. We evaluated these methods using a variety of metrics. Four contributors conducted primary analyses on the real data, and the other two research groups used the simulated data with and without knowledge of the underlying simulation model. One group used the answers to the simulated data to assess power and type I errors. Although the MLMs applied were substantially different, each research group concluded that MLMs have advantages over standard statistical approaches with these high-dimensional data.

An exploration of heterogeneity in genetic analysis of complex pedigrees: linkage and association using whole genome sequencing data in the MAP4 region.

We conduct pedigree-based linkage and association analyses of simulated systolic blood pressure data in the nonascertained large Mexican American pedigrees provided by Genetic Analysis Workshop 18, focusing on observed sequence variants in MAP4 on chromosome 3. Because pedigrees are large and sequence data have been completed by imputation, it is feasible to conduct analysis for each pedigree separately as well as for all pedigrees combined. We are interested in quantifying and explaining between-pedigree heterogeneity in linkage and association signals. To this end, we first examine minor allele frequency differences between pedigrees. In some of the pedigrees, rare and low-frequency variants occur at a higher prevalence than in all pedigrees combined. In simulation replicate 1, we conduct variance-components linkage and association analysis of all 894 MAP4 variants to compare analytic approaches in single pedigree and combined analysis. In all 200 replicates, we similarly examine the 15 causal variants in MAP4 known under the generating model. We illustrate how random allele frequency variation among pedigrees leads to heterogeneity in pedigree-specific linkage and association signals.

Multiphase analysis by linkage, quantitative transmission disequilibrium, and measured genotype: systolic blood pressure in complex Mexican American pedigrees.

We apply a multiphase strategy for pedigree-based genetic analysis of systolic blood pressure data collected in a longitudinal study of large Mexican American pedigrees. In the first phase, we conduct variance-components linkage analysis to identify regions that may harbor quantitative trait loci. In the second phase, we carry out pedigree-based association analysis in a selected region with common and low-frequency variants from genome-wide association studies and whole genome sequencing data. Using sequencing data, we compare approaches to pedigree analysis in a 10 megabase candidate region on chromosome 3 harboring a gene previously identified by a consortium for blood pressure genome-wide association studies. We observe that, as expected, the measured genotype analysis tends to provide larger signals than the quantitative transmission disequilibrium test. We also observe that while linkage signals are contributed by common variants, strong associations are found mainly at rare variants. Multiphase analysis can improve computational efficiency and reduce the multiple testing burden.

Estimating and adjusting for ancestry admixture in statistical methods for relatedness inference, heritability estimation, and association testing.

It is well known that genetic association studies are not robust to population stratification. Two widely used approaches for the detection and correction of population structure are principal component analysis and model-based estimation of ancestry. These methods have been shown to give reliable inference on population structure in unrelated samples. We evaluated these two approaches in Mexican American pedigrees provided by the Genetic Analysis Workshop 18. We also estimated identity-by-descent sharing probabilities and kinship coefficients, with adjustment for ancestry admixture, to confirm documented pedigree relationships as well as to identify cryptic relatedness in the sample. We also estimated the heritability of the first simulated replicate of diastolic blood pressure (DBP). Finally, we performed an association analysis with simulated DBP, comparing the performance of an association method that corrects for population structure but does not account for relatedness to a method that adjusts for both population and pedigree structure. Analyses with simulated DBP were performed with knowledge of the underlying trait model.

Whole genome sequencing data from pedigrees suggests linkage disequilibrium among rare variants created by population admixture.

Next-generation sequencing technologies have been designed to discover rare and de novo variants and are an important tool for identifying rare disease variants. Many statistical methods have been developed to test, using next-generation sequencing data, for rare variants that are associated with a trait. However, many of these methods make assumptions that rare variants are in linkage equilibrium in a gene. In this report, we studied whether transmitted or untransmitted haplotypes carry an excess of rare variants using the whole genome sequencing data of 15 large Mexican American pedigrees provided by the Genetic Analysis Workshop 18. We observed that an excess of rare variants are carried on either transmitted or nontransmitted haplotypes from parents to offspring. Further analyses suggest that such nonrandom associations among rare variants can be attributed to population admixture and single-nucleotide variant calling errors. Our results have significant implications for rare variant association studies, especially those conducted in admixed populations.

Evaluation of TRAF6 in a large multiancestral lupus cohort

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. We undertook to study the role of TRAF6 as a candidate gene for SLE, since it plays a major role in several signaling pathways that are important for immunity and organ development. Fifteen single-nucleotide polymorphisms (SNPs) across TRAF6 were evaluated in 7,490 SLE patients and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. Evidence of associations was detected in multiple SNPs. The best overall P values were obtained for SNPs rs5030437 and rs4755453 (P = 7.85 × 10(-5) and P = 4.73 × 10(-5) , respectively) without significant heterogeneity among populations (P = 0.67 and P = 0.50, respectively, in Q statistic). In addition, SNP rs540386, which was previously reported to be associated with rheumatoid arthritis (RA), was found to be in linkage disequilibrium with these 2 SNPs (r(2) = 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis P = 9.15 × 10(-4) , OR 0.89 [95% CI 0.83-0.95]). The presence of thrombocytopenia improved the overall results in different populations (meta-analysis P = 1.99 × 10(-6) , OR 0.57 [95% CI 0.45-0.72], for rs5030470). Finally, evidence of family-based association in 34 African American pedigrees with the presence of thrombocytopenia was detected in 1 available SNP (rs5030437) with a Z score magnitude of 2.28 (P = 0.02) under a dominant model. Our data indicate the presence of association of TRAF6 with SLE, consistent with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.

Establishing a community partnership to optimize recruitment of African American pedigrees for a genetic epidemiology study

We developed a breast cancer genetic epidemiology study in collaboration with a community partnership to optimize recruitment and participation of African American women. We recognized that recruitment of relatives for a family-based study was a unique challenge in this minority group in the USA. Through an established partnership with The National Witness Project, we convened focus groups to identify potential recruitment challenges and issues related to decisions about study participation that may be unique to African Americans and family-based recruitment. Using the PEN-3 model, we analyzed qualitative data and applied the thematic findings to our recruitment protocol in order to mitigate potential recruitment challenges. The most relevant positive themes included a need for research and education and potential benefit to future generations. Negative themes included communication barriers in sharing disease status within a family and historical issues such as fatalistic attitudes and shamefulness of cancer. Collaboration with community partners allowed for development of culturally appropriate recruitment strategies for African American breast cancer survivors and their family members for a genetic epidemiology study. Understanding factors unique to family-based recruitment in the USA is a significant factor in enhancing participation of under-represented minorities in future genetic studies.

A narrow and highly significant linkage signal for severe bipolar disorder in the chromosome 5q33 region in Latin American pedigrees

We previously reported linkage of bipolar disorder to 5q33-q34 in families from two closely related population isolates, the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (CO). Here we present follow up results from fine-scale mapping in large CVCR and CO families segregating severe bipolar disorder, BP-I, and in 343 population trios/duos from CVCR and CO. Employing densely spaced SNPs to fine map the prior linkage peak region increases linkage evidence and clarifies the position of the putative BP-I locus. We performed two-point linkage analysis with 1134 SNPs in an approximately 9 Mb region between markers D5S410 and D5S422. Combining pedigrees from CVCR and CO yields a LOD score of 4.9 at SNP rs10035961. Two other SNPs (rs7721142 and rs1422795) within the same 94 kb region also displayed LOD scores greater than 4. This linkage peak coincides with our prior microsatellite results and suggests a narrowed BP-I susceptibility regions in these families. To investigate if the locus implicated in the familial form of BP-I also contributes to disease risk in the population, we followed up the family results with association analysis in duo and trio samples, obtaining signals within 2 Mb of the peak linkage signal in the pedigrees; rs12523547 and rs267015 (P = 0.00004 and 0.00016, respectively) in the CO sample and rs244960 in the CVCR sample and the combined sample, with P = 0.00032 and 0.00016, respectively. It remains unclear whether these association results reflect the same locus contributing to BP susceptibility within the extended pedigrees.

Genetic epidemiology of subclinical cardiovascular disease in the diabetes heart study.

A genome-wide linkage scan of 357 European American (EA) and 72 African American (AA) pedigrees multiplex for type 2 diabetes mellitus (T2DM) was performed with multipoint nonparametric QTL linkage analysis. Four subclinical measures of cardiovascular disease (CVD): coronary artery (CCP), carotid artery (CarCP), and abdominal aortic calcified plaque (AACP) and carotid artery intima-media thickness (IMT) were mapped. Analyses were adjusted for age, gender, body mass index, and (if appropriate) ethnicity and diabetes status. Evidence for linkage was observed in EA T2DM subjects to CarCP near 16p13 (LOD=4.39 at 8.4 cM; P = 0.00001). When all EA subjects were included, the LOD score was 2.52, suggesting an amplification of the linkage by diabetes. Linkage analysis of a principal components measure of vascular calcium (LOD = 3.85 at 9.3 cM on 16p in EA T2DM subjects) and bivariate analysis of CarCP X IMT (LOD = 3.77 at 9.3 cM on 16p in EA T2DM subjects) were consistent with this linkage. In addition, evidence for linkage was observed with CCP near D15S1515 (LOD = 2.34) in EAs. Additional loci on chromosomes 1, 2, 7, 10, 13, and 21 had LODs > 2.0. The identification of trait-determining polymorphisms underlying these linkages will help delineate risk factors for CVD in T2DM and the general population.

Genome Scan for Loci Predisposing to Anxiety Disorders Using a Novel Multivariate Approach: Strong Evidence for a Chromosome 4 Risk Locus

We conducted a 10-centimorgan linkage autosomal genome scan in a set of 19 extended American pedigrees (219 subjects) ascertained through probands with panic disorder. Several anxiety disorders--including social phobia, agoraphobia, and simple phobia--in addition to panic disorder segregate in these families. In previous studies of this sample, linkage analyses were based separately on each of the individual categorical affection diagnoses. Given the substantial comorbidity between anxiety disorders and their probable shared genetic liability, it is clear that this method discards a considerable amount of information. In this article, we propose a new approach that considers panic disorder, simple phobia, social phobia, and agoraphobia as expressions of the same multivariate, putatively genetically influenced trait. We applied the most powerful multipoint Haseman-Elston method, using the grade of membership score generated from a fuzzy clustering of these phenotypes as the dependent variable in Haseman-Elston regression. One region on chromosome 4q31-q34, at marker D4S413 (with multipoint and single-point nominal P values < .00001), showed strong evidence of linkage (genomewide significance at P<.05). The same region is known to be the site of a neuropeptide Y receptor gene, NPY1R (4q31-q32), that was recently connected to anxiolytic-like effects in rats. Several other regions on four chromosomes (4q21.21-22.3, 5q14.2-14.3, 8p23.1, and 14q22.3-23.3) met criteria for suggestive linkage (multipoint nominal P values < .01). Family-by-family analysis did not show any strong evidence of heterogeneity. Our findings support the notion that the major anxiety disorders, including phobias and panic disorder, are complex traits that share at least one susceptibility locus. This method could be applied to other complex traits for which shared genetic-liability factors are thought to be important, such as substance dependencies.

Northern sun, southern moon: Europe's reinvention of jazz

Until the 1960s American jazz, for all its improvisational and rhythmic brilliance, remained rooted in formal Western conventions originating in ancient Greece and early Christian plainchant. At the same time European jazz continued to follow the American model. When the creators of so-called free jazz--Ornette Coleman, Cecil Taylor, John Coltrane, Albert Ayler, Sun Ra, Anthony Braxton, and others--liberated American jazz from its Western ties, European musicians found their own distinctive voices and created a vital, innovative, and independent jazz culture. Northern Sun, Southern Moon examines this pan-Eurasian musical revolution. Author and musician Mike Heffley charts its development in Scandinavia, Holland, England, France, Italy, and especially (former East and West) Germany. He then follows its spread to former Eastern-bloc countries. Heffley brings to life an evolving musical phenomenon, situating European jazz in its historical, social, political, and cultural contexts and adding valuable material to the still-scant scholarship on improvisation. He reveals a Eurasian genealogy worthy of jazz's well-established African and American pedigrees and proposes startling new implications for the histories of both Western music and jazz.