Head injury, α-synuclein genetic variability and Parkinson's disease.

BACKGROUND AND PURPOSE: Head injury has been linked to Parkinson's disease (PD) in some but not all studies. Differences in the genetic and environmental susceptibility to PD between populations might be one explanation. The joint effects of head injuries and SNCA genetic variants were investigated. METHODS: From 2001 to 2012, 561 incident idiopathic PD cases and 721 population controls from central California were enrolled. Subjects reported on head injuries throughout their lifetime and were assessed for genetic variability in the SNCA 5' region (D4S3481; Rep1) and 3' untranslated region (rs356165). In unconditional logistic regression models adjusted for confounders, interactions between head injuries and genetic risk variants were investigated. RESULTS: Parkinson's disease risk in individuals with head injury who are carriers of at least one 263 bp allele in D4S3481 or rs356165 variants was 3-4.5-fold higher compared with non-carriers without head injuries. However, tests for interaction between head injury and SNCA D4S3481or rs356165 were not statistically significant. CONCLUSIONS: Our study finds some evidence that head injury and D4S3481 or rs356165 variants jointly increase the risk of PD but little evidence of interaction.

Engineering polarization rotation in a ferroelectric superlattice.

A key property that drives research in ferroelectric perovskite oxides is their strong piezoelectric response in which an electric field is induced by an applied strain, and vice versa for the converse piezoelectric effect. We have achieved an experimental enhancement of the piezoelectric response and dielectric tunability in artificially layered epitaxial PbTiO(3)/CaTiO(3) superlattices through an engineered rotation of the polarization direction. As the relative layer thicknesses within the superlattice were changed from sample to sample we found evidence for polarization rotation in multiple x-ray diffraction measurements. Associated changes in functional properties were seen in electrical measurements and piezoforce microscopy. The results demonstrate a new approach to inducing polarization rotation under ambient conditions in an artificially layered thin film.

Ferroelectric PbTiO3/SrRuO3 superlattices with broken inversion symmetry.

We have fabricated PbTiO3/SrRuO3 superlattices with ultrathin SrRuO3 layers. Because of the superlattice geometry, the samples show a large anisotropy in their electrical resistivity, which can be controlled by changing the thickness of the PbTiO3 layers. Therefore, along the ferroelectric direction, SrRuO3 layers can act as dielectric, rather than metallic, elements. We show that, by reducing the concentration of PbTiO3, an increasingly important effect of polarization asymmetry due to compositional inversion symmetry breaking occurs. The results are significant as they represent a new class of ferroelectric superlattices, with a rich and complex phase diagram. By expanding our set of materials we are able to introduce new behaviors that can only occur when one of the materials is not a perovskite titanate. Here, compositional inversion symmetry breaking in bicolor superlattices, due to the combined variation of A and B site ions within the superlattice, is demonstrated using a combination of experimental measurements and first principles density functional theory.

Dissecting prenatal, postnatal, and inherited effects: ART and design.

With the failure of common variants alone to explain the bulk of trait heritability, it becomes more important to understand the contribution of maternally inherited effects, prenatal effects, and postnatal environmental effects. These effects can be disentangled by studying families containing children conceived by assisted reproductive technologies (ART). We propose and develop a model that is an extension of the variance component model commonly used in pedigree analysis. Our model is flexible enough to allow any number of family members and degrees of relationship; thus, researchers can use both small and extended families simultaneously. Simulations demonstrate that our method has appropriate statistical properties and is robust to model misspecification and accurate in the presence of missing data. Most importantly, our method is able to disentangle maternally inherited effects from prenatal effects, which are confounded in traditional family studies. Our analyses also provide guidance to researchers designing studies that will use ART families to clarify genetic and environmental factors underlying traits.

Penalized regression for genome-wide association screening of sequence data.

Whole exome and whole genome sequencing are likely to be potent tools in the study of common diseases and complex traits. Despite this promise, some very difficult issues in data management and statistical analysis must be squarely faced. The number of rare variants identified by sequencing is apt to be much larger than the number of common variants encountered in current association studies. The low frequencies of rare variants alone will make association testing difficult. This article extends the penalized regression framework for model selection in genome-wide association data to sequencing data with both common and rare variants. Previous research has shown that lasso penalties discourage irrelevant predictors from entering a model. The Euclidean penalties dealt with here group variants by gene or pathway. Pertinent biological information can be incorporated by calibrating penalties by weights. The current paper examines some of the tradeoffs in using pure lasso penalties, pure group penalties, and mixtures of the two types of penalty. All of the computational and statistical advantages of lasso penalized estimation are retained in this richer setting. The overall strategy is implemented in the free statistical genetics analysis software MENDEL and illustrated on both simulated and real data.

TCF7L2 is associated with high serum triacylglycerol and differentially expressed in adipose tissue in families with familial combined hyperlipidaemia.

AIMS/HYPOTHESIS: Common DNA variants of the transcription factor 7-like 2 gene (TCF7L2) are associated with type 2 diabetes. Familial combined hyperlipidaemia (FCHL) is characterised by hypertriacylglycerolaemia, hypercholesterolaemia, or both. Additionally, disturbances in glucose metabolism are commonly seen in FCHL. Therefore, we hypothesised that TCF7L2 may contribute to the genetic susceptibility for this common dyslipidaemia. METHODS: We investigated the effect of the TCF7L2 variants, rs7903146 and rs12255372, on FCHL and its component traits triacylglycerol (TG), total cholesterol (TC) and apolipoprotein B (ApoB) in 759 individuals from 55 Mexican families. As a replication sample, 719 individuals from 60 Finnish FCHL families were analysed. We also used quantitative RT-PCR to evaluate the transcript levels of TCF7L2 in 47 subcutaneous fat biopsies from unrelated Mexican FCHL and normolipidaemic participants. RESULTS: Significant evidence for association was observed for high TG for the T alleles of rs7903146 and rs12255372 (p = 0.005 and p = 0.01) in Mexican FCHL families. No evidence for association was observed for FCHL, TC, ApoB or glucose in Mexicans. When testing rs7903146 and rs12255372 for replication in Finnish FCHL families, these single nucleotide polymorphisms were associated with TG (p = 0.01 and p = 0.007). Furthermore, we observed statistically significant decreases in the mRNA levels (p = 0.0002) of TCF7L2 in FCHL- and TG-affected individuals. TCF7L2 expression was not altered by the SNP genotypes. CONCLUSIONS/INTERPRETATION: These data show that rs7903146 and rs12255372 are significantly associated with high TG in FCHL families from two different populations. In addition, significantly decreased expression of TCF7L2 was observed in TG- and FCHL-affected individuals.

Genetic influences in the aetiology of anteromedial osteoarthritis of the knee.

We report a study of 112 patients with primary anteromedial osteoarthritis of the knee and their families. Sibling risk was determined using randomly selected single siblings. Spouses were used as controls. The presence of symptomatic osteoarthritis was determined using an Oxford knee score of > or= 29 supported by a Kellgren and Lawrence radiological score of II or greater. Using Fisher's exact test we found that there was a significant increased risk of anteromedial osteoarthritis (OA) relative to the control group (p = 0.031). The recurrence risk of anteromedial OA to siblings was 3.21 (95% confidence interval 1.12 to 9.27). These findings imply that genetic factors may play a major role in the development of anteromedial OA of the knee.

Genetic association analysis of LRCH1 as an osteoarthritis susceptibility locus.

OBJECTIVE: A genetic association with knee osteoarthritis (OA) of a single nucleotide polymorphism (SNP) in intron 1 of the LRCH1 gene was recently reported in a UK Caucasian case-control sample and confirmed in a Newfoundland Caucasian sample. Our objective was to assess whether the SNP was associated with OA in our large UK Caucasian sample. METHODS: The SNP was genotyped in 1521 cases that had undergone elective joint replacement of the hip (1098 cases), of the knee (340 cases) or of the hip and knee (83 cases) due to end-stage primary OA. The SNP was also genotyped in 736 controls of similar ages in the cases. RESULTS: There was no significant difference (all P-values >0.05) in genotype or allele frequencies between our cases and our controls. There was also no significant difference when the cases were stratified by sex, by joint replaced or by sex combined with joint replaced. CONCLUSION: Our data on 2257 individuals implies that the LRCH1 intron 1 SNP is not a risk factor for OA aetiology of the knee or of the hip in our UK Caucasian sample.

Incorporating serotypes into family based association studies using the MFG test.

Family based association tests are widely used to detect genetic effects. The focus of this paper is the maternal-fetal genotype (MFG) incompatibility test, a family based association test which can be used to detect genetic effects that contribute to disease, including alleles in the child that increase disease risk, maternal alleles that increase disease risk in the child, and maternal-fetal genotype incompatibilities. Consideration of incomplete data resulting from using serotypes could expand the power of the MFG test for detecting genetic effects. Serotypes may be all that are available in certain families, or preferred because of convenience or low cost, and thus a modification of the MFG test will allow optimal use of such data. The modified MFG likelihood can accommodate the incomplete data that result from using serotypes rather than the corresponding codominant genotypes. The modified MFG test was evaluated with serotypes and genotypes from families with members affected with schizophrenia. In addition, simulation studies were performed. Results of the data analyses and simulation studies showed that serotypes can be used to augment genotypes within a sample, to increase power to detect effects when the candidate gene produces serotypes.

The CALM1 core promoter polymorphism is not associated with hip osteoarthritis in a United Kingdom Caucasian population.

OBJECTIVE: A convincing genetic association with hip osteoarthritis (OA) of a functional single nucleotide polymorphism (SNP) in the core promoter of the calmodulin 1 gene CALM1 was recently reported in a Japanese population. The T-allele of the SNP encoded OA susceptibility and this was mediated by a reduced expression of CALM1. Our objective was to assess whether the SNP was also associated with hip OA in UK Caucasians. METHODS: The SNP was genotyped in 920 cases that had undergone elective joint replacement of the hip due to end-stage primary OA and in 752 age-matched controls. RESULTS: Our study had greater than 97% power to observe an effect comparable to that seen in the Japanese study. However, there was no significant difference (P< or =0.05) in genotype or allele frequencies between our cases and our controls. There was also no significant difference when the cases were stratified by sex. CONCLUSION: Our data on a cohort of 1672 individuals implies that the CALM1 core promoter polymorphism is not a risk factor for OA etiology in Caucasians. Our study does not call in to question the veracity of the Japanese report. Instead it highlights the heterogeneous nature of OA genetic susceptibility.

Fishing for pleiotropic QTLs in a polygenic sea.

The application of factor analysis to human genetics has the potential to discover the coordinated control of multiple traits by common environment, common polygenes, or a single major gene. Classical factor analysis explains the covariation among the components of a random vector by approximating the vector by a linear transformation of a small number of uncorrelated factors. In the current paper we show how factor analysis dovetails with the classical variance decompositions of biometrical genetics. To explore the relationships between related quantitative variables, and avoid complicated positive definiteness constraints, we employ Cholesky and factor analytic decompositions. We derive an ECM algorithm and a competing quasi-Newton algorithm for estimating parameters by maximum likelihood and propose tactics for selecting initial parameter values. We also show how parameter asymptotic standard errors under these parameterizations propagate to asymptotic standard errors of the underlying variance components. Our genetic analysis program Mendel, which now incorporates the program Fisher, has performed well on a variety of data sets. We illustrate our methods, algorithms, and models on two data sets: a bivariate quantitative genetic example using total finger ridge count data and a multivariate linkage example using insulin resistance data.

SNP haplotypes in the angiotensin I-converting enzyme (ACE) gene: analysis of Nigerian family data using gamete competition models.

Gamete competition models were used to explore the relationships between 13 ACE gene polymorphisms and plasma ACE concentration in a set of Nigerian families. Several markers in the 5' and 3' regions of the gene were significantly associated with ACE concentration (P < 10(-4)). Multi-locus genotypes comprising different combinations of markers from the 5' UTR and the 3' region of the gene were also analysed; in addition to G2350A, in the 3' region, two markers from the 5' UTR (A-5466C and A-240T) were found to be associated with ACE concentration. These results are consistent with reports that have suggested the presence of at least two ACE-linked QTLs, and demonstrate the utility of gamete competition models in the exploratory investigation of the relationship between a quantitative trait and multiple variants in a small genomic region.

Chromosome 1 loci in Finnish schizophrenia families.

We have earlier reported evidence for linkage to two regions on chromosome 1q32--q42 in schizophrenia families collected for two separate studies in Finland. Here we report the results of a fine mapping effort aimed at further definition of the chromosomal region of interest using a large, population-based study sample (221 families, 557 affected individuals). Most affecteds (78%) had a DSM-IV schizophrenia diagnosis and the remaining had schizophrenia spectrum disorders. We genotyped a total of 147 microsatellite markers on a wide 45 cM region of chromosome 1q. The results were analyzed separately for families originating from an internal isolate of Finland and for families from the rest of Finland, as well as for all families jointly. We used traditional two-point linkage analysis, SimWalk2 multipoint analysis and a novel gamete-competition association/linkage method. Evidence for linkage was obtained for one locus in the combined sample (Z(max) = 2.71, D1S2709) and in the nuclear families from outside the internal isolate (Z(max) = 3.21, D1S2709). In the families from the internal isolate the strongest evidence for linkage was obtained with markers located 22 cM centromeric from this marker (Z(max) = 2.30, D1S245). Multipoint analysis also indicated these loci. Some evidence for association with several markers was observed using the gamete-competition method. Interestingly, the strongest evidence for linkage in the combined study sample was obtained for marker D1S2709, which is an intragenic marker of the DISC1 gene, previously suggested as a susceptibility gene for schizophrenia. These results are consistent with the presence of susceptibility gene(s) in this chromosomal region, a result also implied in other recent family studies of schizophrenia.

Bayesian selection of continuous-time Markov chain evolutionary models.

We develop a reversible jump Markov chain Monte Carlo approach to estimating the posterior distribution of phylogenies based on aligned DNA/RNA sequences under several hierarchical evolutionary models. Using a proper, yet nontruncated and uninformative prior, we demonstrate the advantages of the Bayesian approach to hypothesis testing and estimation in phylogenetics by comparing different models for the infinitesimal rates of change among nucleotides, for the number of rate classes, and for the relationships among branch lengths. We compare the relative probabilities of these models and the appropriateness of a molecular clock using Bayes factors. Our most general model, first proposed by Tamura and Nei, parameterizes the infinitesimal change probabilities among nucleotides (A, G, C, T/U) into six parameters, consisting of three parameters for the nucleotide stationary distribution, two rate parameters for nucleotide transitions, and another parameter for nucleotide transversions. Nested models include the Hasegawa, Kishino, and Yano model with equal transition rates and the Kimura model with a uniform stationary distribution and equal transition rates. To illustrate our methods, we examine simulated data, 16S rRNA sequences from 15 contemporary eubacteria, halobacteria, eocytes, and eukaryotes, 9 primates, and the entire HIV genome of 11 isolates. We find that the Kimura model is too restrictive, that the Hasegawa, Kishino, and Yano model can be rejected for some data sets, that there is evidence for more than one rate class and a molecular clock among similar taxa, and that a molecular clock can be rejected for more distantly related taxa.

Fine mapping of Hyplip1 and the human homolog, a potential locus for FCHL.

Familial combined hyperlipidemia (FCHL) is a common genetic dyslipidemia predisposing to premature coronary heart disease (CHD). We previously identified a locus for FCHL on human Chromosome (Chr) 1q21-q23 in 31 Finnish FCHL families. We also mapped a gene for combined hyperlipidemia (Hyplip1) to a potentially orthologous region of mouse Chr 3 in the HcB-19/Dem mouse model of FCHL. The human FCHL locus was, however, originally mapped about 5 Mb telomeric to the synteny border, the centromeric part of which is homologous to mouse Chr 3 and the telomeric part to mouse Chr 1. To further localize the human Hyplip1 homolog and estimate its distance from the peak linkage markers, we fine-mapped the Hyplip1 locus and defined the borders of the region of conserved synteny between human and mouse. This involved establishing a physical map of a bacterial artificial chromosome (BAC) contig across the Hyplip1 locus and hybridizing a set of BACs to both human and mouse chromosomes by fluorescence in situ hybridization (FISH). We narrowed the location of the mouse Hyplip1 gene to a 1.5-cM region that is homologous only with human 1q21 and within approximately 5-10 Mb of the peak marker for linkage to FCHL. FCHL is a complex disorder and this distance may, thus, reflect the well-known problems hampering the mapping of complex disorders. Further studies identifying and sequencing the Hyplip1 gene will show whether the same gene predisposes to hyperlipidemia in human and mouse.

Primate DAX1, SRY, and SOX9: evolutionary stratification of sex-determination pathway.

The molecular evolution of DAX1, SRY, and SOX9, genes involved in mammalian sex determination, was examined in six primate species. DAX1 and SRY have been added to the X and Y chromosomes, respectively, during mammalian evolution, whereas SOX9 remains autosomal. We determined the genomic sequences of DAX1, SRY, and SOX9 in all six species, and calculated K(a), the number of nonsynonymous substitutions per nonsynonymous site, and compared this with the K(s), the number of synonymous substitutions per synonymous site. Phylogenetic trees were constructed by means of the DAX1, SRY, and SOX9 coding sequences, and phylogenetic analysis was performed using maximum likelihood. Overall measures of gene and protein similarity were closer for DAX1 and SOX9, but DAX1 exhibited nonsynonymous amino acid substitutions at an accelerated frequency relative to synonymous changes, similar to SRY and significantly higher than SOX9. We conclude that, at the protein level, DAX1 and SRY are under less selective pressure to remain conserved than SOX9, and, therefore, diverge more across species than does SOX9. These results are consistent with evolutionary stratification of the mammalian sex determination pathway, analogous to that for sex chromosomes.

SNPing away at candidate genes.

We develop regression methodology to identify subsets of single nucleotide polymorphisms (SNPs) within candidate genes related to quantitative traits and apply our methods to the simulated Genetic Analysis Workshop (GAW) 12 data set. In the data set we find 694 SNP loci with minimum allele frequencies of at least 0.01. We assume an additive casual model between these SNPs and all five quantitative traits. After initial screening using one-way analysis of variance, we employ a computationally efficient, simulated annealing algorithm to select among all possible subsets of SNP loci, using a generalization of Mallows' Cp as our optimality criterion. The simple transition kernel we develop evaluates new subsets in O(1), by requiring just three arithmetic operations to calculate the proposed RSS based on the Gauss-Jordan pivot. We identify an SNP loci located at 6-5782 related to traits 2 and 3 and several sites on gene 2 related to trait 5 using a subsample of 1,000 individuals and the full data set (n = 8,250) for comparison.

SNPs and snails and puppy dogs' tails: analysis of SNP haplotype data using the gamete competition model.

The gamete competition model is a likelihood version of the transmission disequilibrium test (TDT) that is inspired by conditional logistic regression and the Bradley-Terry ranking procedure. In family-based association studies, both the TDT and the gamete competition model apply directly to data on a single nucleotide polymorphism (SNP). Because any given SNP has limited polymorphism, it is tempting to collect several SNPs within a gene into a single super marker whose alleles are haplotypes. Unfortunately, this tactic wreaks havoc with the traditional TDT, which requires codominant markers (Spielman et al. 1993; Terwilliger & Ott, 1992). Eliminating phase ambiguities by assigning haplotypes to individuals before conducting the TDT may give misleading results because only the most probable haplotypes are then considered. Because pedigree implementations of the gamete competition model can accommodate dominant as well as codominant markers, they circumvent the phase problem by including all possible phases weighted by their estimated frequencies.

End-stage coxarthrosis and gonarthrosis. Aetiology, clinical patterns and radiological features of idiopathic osteoarthritis.

OBJECTIVES: To determine and compare the aetiological background, clinical patterns and radiological features of idiopathic osteoarthritis (OA) of the hip and the knee warranting arthroplasty. METHODS: A total of 402 Caucasians consecutively undergoing total hip replacement (THR) or total knee replacement (TKR) for idiopathic OA at a major centre was surveyed. RESULTS: Previous joint injury was more common in the TKR group (P < 0.0001). However, both groups manifested a mixed occupational background, body mass indices similar to the general population and a predominance of females (F:M = 1.3-1.4:1). The TKR group had a significantly younger age of symptom onset (56 yr) than the THR group (61 yr) but both groups had a tendency to bilateral arthroplasty (33%), nodal involvement (54-59%), a significant excess of right-sided replacements (1.8:1, THR; 2.2:1, TKR) and similar levels of pre-operative pain and disability. Up to 40% of hips manifested acetabular dysplasia and 10% possible previous slipped upper femoral epiphyses. Eighty-five per cent with end-stage coxarthrosis or gonarthrosis had an identical pattern of radiographic disease contralaterally. CONCLUSIONS: Our data suggest the importance of a constitutional tendency to idiopathic, end-stage OA, a disorder traditionally associated with environmental factors leading to 'wear and tear'.

Linkage analysis of candidate genes as susceptibility loci for osteoarthritis-suggestive linkage of COL9A1 to female hip osteoarthritis.

OBJECTIVE: To examine 11 candidate genes as susceptibility loci for osteoarthritis (OA). METHODS: A total of 481 families have been ascertained in which at least two siblings have had joint replacement surgery of the hip, or knee, or hip and knee for idiopathic OA. Each candidate gene was targeted using one or more intragenic or closely linked microsatellite marker. The linkage data were analysed unstratified and following stratification by sex and by joint replaced (hip or knee). RESULTS: The analyses revealed suggestive linkage of the type IX collagen gene COL9A1 (6q12-q13) to a subset of 132 families that contained affected females who were concordant for hip OA (female-hip) with a P-value of 0.00053 and logarithm of the odds (LOD) score of 2.33 [corrected P-value of 0. 0016, corrected LOD score of 1.85]. CONCLUSIONS: COL9A1 may therefore be a susceptibility locus for female hip OA. In addition, there was weak evidence of linkage to HLA/COL11A2 (6p21.3) in female hip OA with a corrected P-value of 0.016.