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PubMed2005

Familiality of temperament in bipolar disorder: support for a genetic spectrum.

BACKGROUND: The array of different diagnoses and clinical presentations seen in the family members of bipolar probands suggests a quantitative or spectrum phenotype. Consistent with this idea, it has been proposed that an underlying quantitative variation in temperament may be the primary phenotype that is genetically transmitted and that it in turn predisposes to bipolar disorder (BP). Choosing the appropriate phenotypic model for BP is crucial for success in genetic mapping studies. To test this theory, various measures of temperament were examined in the family members of bipolar probands. We predicted that a gradient of scores would be observed from those with BP to those with major depression to unaffected relatives to controls. METHODS: Members of 85 bipolar families and 63 control subjects were administered clinical interviews for diagnosis (SCID) and two temperament assessments, the TEMPS-A and TCI-125. Subjects with BP, major depressive disorder, unaffected relatives, and controls were compared on each temperament scale and on eight factors extracted from a joint factor analysis of the TEMPS-A and TCI-125. RESULTS: The four groups were found to be significantly different and with the expected order of average group scores for four of the TEMPS-A scales, three of the TCI-125 scales, and one of the extracted factors. On the fifth TEMPS-A scale, hyperthymic, controls scored higher than the other three subject groups contrary to expectations. Significant differences were seen between unaffected relatives and controls on the hyperthymic scale and on the first extracted factor, anxious/reactive. LIMITATIONS: Controls were mainly recruited through advertisements, which may have introduced an ascertainment bias. It is also possible that mood state at the time of completing the questionnaire influenced subject's rating of their temperament. Additionally, bipolar I and bipolar II subjects were placed in the same group even though they had some differing clinical features. CONCLUSIONS: Our data support the theory that some dimensions of temperament are transmitted in families as quantitative traits that are part of a broader bipolar spectrum. In particular, the hyperthymic scale of the TEMPS-A and the anxious/reactive extracted factor distinguished unaffected relatives from controls. The hyperthymic scale yielded results opposite to expectation with controls higher than any family group. This may be an artifact of the self-rated form of the questionnaire, a consequence of our grouping bipolar I and II subjects together, or the result of a "protective" factor and bears further study. Nevertheless, both of these scales may be useful quantitative traits for genetic mapping studies.

Bipolar Disorder↗
PubMed2003

Genome sharing in large pedigrees: multiple imputation of ibd for linkage detection.

Our objective is the development of robust methods for assessment of evidence for linkage of loci affecting a complex trait to a marker linkage group, using data on extended pedigrees. Using Markov chain Monte Carlo (MCMC) methods, it is possible to sample realizations from the distribution of gene identity by descent (IBD) patterns on a pedigree, conditional on observed data YM at multiple marker loci. Measures of gene IBDW which capture joint genome sharing in extended pedigrees often have unknown and highly skewed distributions, particularly when conditioned on marker data. MCMC provides a direct estimate of the distribution of such measures. Let W be the IBD measure from data YM, and W* the IBD measure from pseudo-data Y*M simulated with the same data availability and genetic marker model as the true data YM, but in the absence of linkage. Then measures of the difference in distributions of W and W* provide evidence for linkage. This approach extracts more information from the data YM than either comparison to the pedigree prior distribution of W or use of statistics that are expectations of W given the data YM. A small example is presented.

Chromosome Mapping↗
PubMed2006

Multiple hypothesis testing strategies for genetic case-control association studies.

The genetic case-control association study of unrelated subjects is a leading method to identify single nucleotide polymorphisms (SNPs) and SNP haplotypes that modulate the risk of complex diseases. Association studies often genotype several SNPs in a number of candidate genes; we propose a two-stage approach to address the inherent statistical multiple comparisons problem. In the first stage, each gene's association with disease is summarized by a single p-value that controls a familywise error rate. In the second stage, summary p-values are adjusted for multiplicity using a false discovery rate (FDR) controlling procedure. For the first stage, we consider marginal and joint tests of SNPs and haplotypes within genes, and we construct an omnibus test that combines SNP and haplotype analysis. Simulation studies show that when disease susceptibility is conferred by a SNP, and all common SNPs in a gene are genotyped, marginal analysis of SNPs using the Simes test has similar or higher power than marginal or joint haplotype analysis. Conversely, haplotype analysis can be more powerful when disease susceptibility is conferred by a haplotype. The omnibus test tracks the more powerful of the two approaches, which is generally unknown. Multiple testing balances the desire for statistical power against the implicit costs of false positive results, which up to now appear to be common in the literature.

Case-Control Studies↗
PubMed2004

Variation in recombination rate may bias human genetic disease mapping studies.

The availability of the human genome sequence and variability information (as from the International HapMap project) will enhance our ability to map genetic disorders and choose targets for therapeutic intervention. However, several factors, such as regional variation in recombination rate, can bias conclusions from genetic mapping studies. Here, we examine the impact of regional variation in recombination rate across the human genome. Through computer simulations and literature surveys, we conclude that genetic disorders have been mapped to regions of low recombination more often than expected if such diseases were randomly distributed across the genome. This concentration in low recombination regions may be an artifact, and disorders appearing to be caused by a few genes of large effect may be polygenic. Future genetic mapping studies should be conscious of this potential complication by noting the regional recombination rate of regions implicated in diseases.

Bias↗
PubMed2003

Power evaluations for family-based tests of association with incomplete parental genotypes.

While a variety of methods have been developed to deal with incomplete parental genotype information in family-based association tests, sampling design issues with incomplete parental genotype data still have not received much attention. In this article, we present simulation studies with four genetic models and various sampling designs and evaluate power in family-based association studies. Efficiency depends heavily on disease prevalence. With rare diseases, sampling affecteds and their parents is preferred, and three sibs will be required to have close power if parents are unavailable. With more common diseases, sampling affecteds and two sibs will generally be more efficient than trios. When parents are unavailable, siblings need not be phenotyped if the disease is rare, but a loss of power will result with common diseases. Finally, for a class of complex traits where other genetic and environmental factors also cause phenotypic correlation among siblings, little loss of efficiency occurs to rare disease, but substantial loss of efficiency occurs to common disease.

Data Interpretation, Statistical↗
PubMed2026

Polygenic risk scores associate with asthma phenotypes and proteomic analyses implicate IL1R1 in two family-based studies.

Despite its high prevalence and the discovery of hundreds of genetic associations, the genetic determinants and heterogeneous manifestations of asthma remain incompletely understood. Incorporating polygenic risk scores (PRS) into asthma research offers a powerful approach to quantify inherited susceptibility, refine risk profiles, and advance mechanistic understanding of disease development. For this study, we leveraged whole-genome sequencing (WGS) data from two family-based cohorts of childhood asthma - the Genetics of Asthma in Costa Rica Study (GACRS) and the Childhood Asthma Management Program (CAMP) - to examine the transmission profiles of externally derived asthma PRS and their associations with clinical phenotypes in children with asthma. To further elucidate molecular mechanisms, we integrated large-scale external genome-wide association study (GWAS) summary statistics and genetic prediction models of protein abundance in a two-step proteome-wide association study (PWAS) of asthma. Our findings provide robust evidence supporting the validity of externally derived asthma PRS (asthma PRS association p-value p = 10-24 [GACRS and CAMP trios combined] for the Global Biobank Meta-analysis Initiative [GBMI]) and reveal consistent associations with spirometry measures and atopy markers across both studies, as 13 of 21 traits (62%) were significantly associated with the GBMI-PRS in the meta-analysis after multiple-testing correction. Moreover, the results of the integrative proteomic analysis implicate IL-1 signaling in the etiology of asthma, reinforcing the candidacy of IL1R1 antagonists for drug repurposing.

Journal Article↗
PubMed2003

Linkage analysis of quantitative trait loci in the presence of heterogeneity.

Variance component modeling for linkage analysis of quantitative traits is a powerful tool for detecting and locating genes affecting a trait of interest, but the presence of genetic heterogeneity will decrease the power of a linkage study and may even give biased estimates of the location of the quantitative trait loci. Many complex diseases are believed to be influenced by multiple genes and therefore genetic heterogeneity is likely to be present for many real applications of linkage analysis. We consider a mixture of multivariate normals to model locus heterogeneity by allowing only a proportion of the sampled pedigrees to segregate trait-influencing allele(s) at a specific locus. However, for mixtures of normals the classical asymptotic distribution theory of the maximum likelihood estimates does not hold, so tests of linkage and/or heterogeneity are evaluated using resampling methods. It is shown that allowing for genetic heterogeneity leads to an increase in power to detect linkage. This increase is more prominent when the genetic effect of the locus is small or when the percentage of pedigrees not segregating trait-influencing allele(s) at the locus is high.

Chromosome Mapping↗
PubMed2000

Parenting and its effects on children: on reading and misreading behavior genetics.

There is clear evidence that parents can and do influence children. There is equally clear evidence that children's genetic makeup affects their own behavioral characteristics, and also influences the way they are treated by their parents. Twin and adoption studies provide a sound basis for estimating the strength of genetic effects, although heritability estimates for a given trait vary widely across samples, and no one estimate can be considered definitive. This chapter argues that knowing only the strength of genetic factors, however, is not a sufficient basis for estimating environmental ones and indeed, that attempts to do so can systematically underestimate parenting effects. Children's genetic predispositions and their parents' childrearing regimes are seen to be closely interwoven, and the ways in which they function jointly to affect children's development are explored.

Adult↗
PubMed2025

Extracting and calibrating evidence of variant pathogenicity from population biobank data.

Genomic medicine requires a robust evidence base of variant phenotypic impacts, which remains incomplete even in extensively studied genes with monogenic disease associations. Here, we evaluated the broad potential of using population cohort data to identify evidence that can be used in variant assessment. Across 41 genes related to 18 clinically actionable monogenic phenotypes, we calculated variant-level odds ratios of disease enrichment using data from 469,803 UK Biobank participants. We found significant differences in odds ratio values between ClinVar-labeled pathogenic and benign variants in 11 phenotypes, spanning both common and rare disorders. To facilitate clinical translation, we calibrated the strength of evidence provided by variant-level odds ratios to align with American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) interpretation guidelines (PS4 criterion) and found that odds ratios may reach "moderate," "strong," or "very strong" evidence, varying by phenotype and gene. Overall, we found that 2.6% (N = 12,350) of participants harbor a rare variant of uncertain significance (VUS) with at least moderate evidence of pathogenicity-an indication of potentially unrecognized disease risk. Finally, by incorporating computational and functional data alongside population-based odds ratios, we identified variants that met the criteria for clinical reclassification. Notably, using this approach, we identified that 12.4% of rare VUSs in LDLR seen in participants meet diagnostic criteria to be classified as likely pathogenic, demonstrating its potential to scale the reclassification of VUSs.

Humans↗
PubMed1986

Statistical decision rules concerning synteny or independence between markers.

Data on the segregation of human markers in somatic hybrids between permanent rodent cell lines and primary human cells were gathered and statistically analyzed, using various criteria of association. The analysis provides evidence that human chromosomes do not segregate independently in somatic cell hybrids. A statistical decision rule concerning synteny or independence between markers is proposed, and its utility in developing the gene maps of other species by means of somatic cell hybridization is explored.

Animals↗
PubMed1996

Molecular genetics of bipolar disorder.

Bipolar (BP) disorder is a severe mood disorder affecting about 1% of the population. Even though the traditional twin, family, and adoption studies have demonstrated that it is highly heritable, the specific vulnerability genes have so far escaped identification. The early years of molecular genetic studies in BP disorder were hampered by the complexities in the inheritance and phenotype of BP disorder, the poor marker maps and the low informativeness of DNA markers available at that time. The new developments in molecular genetics and statistical analysis methods for complex disorders have provided researchers with better tools to cope with these difficulties. During the past few years, several potential susceptibility loci have been reported in chromosomes 18, 21 and X, and the possible role of trinucleotide repeat expansions in the aetiology of BP disorder has been developed. It seems that the molecular genetics of BP disorder are entering a new era of rapid developments.

Bipolar Disorder↗
PubMed1995

Tryptophanyl-tRNA synthetase crystal structure reveals an unexpected homology to tyrosyl-tRNA synthetase.

BACKGROUND: Tryptophanyl-tRNA synthetase (TrpRS) catalyzes activation of tryptophan by ATP and transfer to tRNA(Trp), ensuring translation of the genetic code for tryptophan. Interest focuses on mechanisms for specific recognition of both amino acid and tRNA substrates. RESULTS: Maximum-entropy methods enabled us to solve the TrpRS structure. Its three parts, a canonical dinucleotide-binding fold, a dimer interface, and a helical domain, have enough structural homology to tyrosyl-tRNA synthetase (TyrRS) that the two enzymes can be described as conformational isomers. Structure-based sequence alignment shows statistically significant genetic homology. Structural elements interacting with the activated amino acid, tryptophanyl-5'AMP, are almost exactly as seen in the TyrRS:tyrosyl-5'AMP complex. Unexpectedly, side chains that recognize indole are also highly conserved, and require reorientation of a 'specificity-determining' helix containing a conserved aspartate to assure selection of tryptophan versus tyrosine. The carboxy terminus, which is disordered and therefore not seen in TyrRS, forms part of the dimer interface in TrpRS. CONCLUSIONS: For the first time, the Bayesian statistical paradigm of entropy maximization and likelihood scoring has played a critical role in an X-ray structure solution. Sequence relatedness of structurally superimposable residues throughout TrpRS and TyrRS implies that they diverged more recently than most aminoacyl-tRNA synthetases. Subtle, tertiary structure changes are crucial for specific recognition of the two different amino acids. The conformational isomerism suggests that movement of the KMSKS loop, known to occur in the TyrRS transition state for amino acid activation, may provide a basis for conformational coupling during catalysis.

Amino Acid Sequence↗
PubMed2002

Mathematics-assisted mapping in analysis of medical disease.

Genetic mapping in analysis of medical disease is performed under several assumptions and (experimental) conditions, which are made about the data in general and the disease in particular. Here we discuss these conditions, what they mean, and what kind of deleterious effects they might have on the analysis. We also illustrate how to proceed and what kind of possibilities the statistical analysis may provide to medical scientists.

Chromosome Mapping↗
PubMed1999

Among-locus variation in Fst: fish, allozymes and the Lewontin-Krakauer test revisited.

Variation among loci in the distribution of allele frequencies among subpopulations is well known; how to tell when the variation exceeds that expected when all loci are subject to uniform evolutionary processes is not well known. If locus-specific effects are important, the ability to detect those effects should vary with the level of gene flow. Populations with low gene flow should exhibit greater variation among loci in Fst than populations with high gene flow, because gene flow acts to homogenize allele frequencies among subpopulations. Here I use Lewontin and Krakauer's k statistic to describe the variance among allozyme loci in 102 published data sets from fishes. As originally proposed, k >> 2 was considered evidence that the variation in Fst among loci is greater than expected from neutral evolution. Although that interpretation is invalid, large differences in k in different populations suggest that locus-specific forces may be important in shaping genetic diversity. In these data, k is not greater for populations with expected low levels of gene flow than for populations with expected high levels of gene flow. There is thus no evidence that locus-specific forces are of general importance in shaping the distribution of allele frequencies at enzyme loci among populations of fishes.

Alleles↗
PubMed2003

Allozyme diversity in Anopheles quadrimaculatus (sensu stricto) populations in northeastern Arkansas.

A comparison of electrophoretically detectable isozyme differences in 6 populations of Anopheles quadrimaculatus (sensu stricto) from northeastern Arkansas was undertaken to test the hypothesis that microgeographic variation in habitat types was promoting significant within- and between-population genetic diversity. Genetic heterogeneity within populations was substantial, with all of the enzyme loci examined having 2-7 alleles and average levels of polymorphisms per population between 54.5 and 72.7%. Heterozygotes made up an average over all loci of between 20.6 and 24.8% of the individuals examined. Only weak evidence was found for gametic disequilibrium between pairs of loci. Neither F-statistic nor genetic distance analysis suggested interpopulation divergence. The FST value averaged over loci was 0.190. All Nei distances for pair-wise population comparisons were greater than 0.010, which was much lower than published values from comparisons between populations belonging to different species of the complex. Divergence was not significantly correlated to either geographic distance or habitat type. Examination of the results suggests that little genetic divergence has occurred between populations of An. quadrimaculatus in northeastern Arkansas, possibly because of the dispersal ability and low level of discrimination between oviposition sites exhibited by this species.

Alleles↗
PubMed1998

Genetic analysis of three South African horse breeds.

Genetic variability at 7 blood-group and 10 biochemical genetic loci was examined in 3 South African horse breeds, the Nooitgedacht, Boerperd and Basuto Pony. Observed heterozygosity for these breeds was intermediate for domestic horses, with the highest heterozygosity in the Boerperd and the lowest in the Basuto Pony. The 3 breeds show greater genetic similarity to each other than to other domestic horse breeds. Compared to other breeds, the South African breeds show greater genetic similarity to breeds such as the Thoroughbred, Holstein, Trakehner and Hanovarian and also to North American breeds such as the Saddlebred, Standardbred and Morgan Horse.

Alleles↗
PubMed1985

A systematic study of HLA class II-beta DNA restriction fragments in insulin-dependent diabetes mellitus.

DNA restriction fragments of the genes encoding HLA class II-beta antigens were compared in 34 patients with insulin-dependent diabetes mellitus and 34 HLA-DR-matched healthy individuals. Ninety-three fragments, determined by six restriction enzymes (EcoRI, EcoRV, HindIII, BamHI, Pvu II, and Taq I), were analyzed: (i) A DR Taq I 12.7-kilobase-pair fragment might be a marker for the extended haplotype HLA-B8, DR3. (ii) In controls, DR4 haplotypes are associated with two distinct clusters of DQ restriction fragments (DQR4 and DQR5). Almost all (94%) DR4 patients belong to the DQR4 and not to the DQR5 cluster. This suggests that, among HLA-DR4 haplotypes, only DQR4 haplotypes are involved in susceptibility to insulin-dependent diabetes mellitus. (iii) A DR Taq I 14.5-kilobase-pair fragment was found to be strongly associated with DQR4, mainly in DR3/DR4 heterozygous patients (P = 5 X 10(-4). However, these results must be interpreted with caution, taking into account the high number of statistical tests performed.

DNA Restriction Enzymes↗