Common SNPs explain a large proportion of the heritability for human height

SNPs discovered by genome-wide association studies (GWASs) account for only a small fraction of the genetic variation of complex traits in human populations. Where is the remaining heritability? We estimated the proportion of variance for human height explained by 294,831 SNPs genotyped on 3,925 unrelated individuals using a linear model analysis, and validated the estimation method with simulations based on the observed genotype data. We show that 45% of variance can be explained by considering all SNPs simultaneously. Thus, most of the heritability is not missing but has not previously been detected because the individual effects are too small to pass stringent significance tests. We provide evidence that the remaining heritability is due to incomplete linkage disequilibrium between causal variants and genotyped SNPs, exacerbated by causal variants having lower minor allele frequency than the SNPs explored to date.

A genome-wide association study of Cloninger's temperament scales: implications for the evolutionary genetics of personality

Variation in personality traits is 30-60% attributed to genetic influences. Attempts to unravel these genetic influences at the molecular level have, so far, been inconclusive. We performed the first genome-wide association study of Cloninger's temperament scales in a sample of 5117 individuals, in order to identify common genetic variants underlying variation in personality. Participants' scores on Harm Avoidance, Novelty Seeking, Reward Dependence, and Persistence were tested for association with 1,252,387 genetic markers. We also performed gene-based association tests and biological pathway analyses. No genetic variants that significantly contribute to personality variation were identified, while our sample provides over 90% power to detect variants that explain only 1% of the trait variance. This indicates that individual common genetic variants of this size or greater do not contribute to personality trait variation, which has important implications regarding the genetic architecture of personality and the evolutionary mechanisms by which heritable variation is maintained.

Common variants in the trichohyalin gene are associated with straight hair in Europeans

Hair morphology is highly differentiated between populations and among people of European ancestry. Whereas hair morphology in East Asian populations has been studied extensively, relatively little is known about the genetics of this trait in Europeans. We performed a genome-wide association scan for hair morphology (straight, wavy, curly) in three Australian samples of European descent. All three samples showed evidence of association implicating the Trichohyalin gene (TCHH), which is expressed in the developing inner root sheath of the hair follicle, and explaining approximately 6% of variance (p=1.5x10(-31)). These variants are at their highest frequency in Northern Europeans, paralleling the distribution of the straight-hair EDAR variant in Asian populations.

Genetic influences on handedness: data from 25,732 Australian and Dutch twin families

Handedness refers to a consistent asymmetry in skill or preferential use between the hands and is related to lateralization within the brain of other functions such as language. Previous twin studies of handedness have yielded inconsistent results resulting from a general lack of statistical power to find significant effects. Here we present analyses from a large international collaborative study of handedness (assessed by writing/drawing or self report) in Australian and Dutch twins and their siblings (54,270 individuals from 25,732 families). Maximum likelihood analyses incorporating the effects of known covariates (sex, year of birth and birth weight) revealed no evidence of hormonal transfer, mirror imaging or twin specific effects. There were also no differences in prevalence between zygosity groups or between twins and their singleton siblings. Consistent with previous meta-analyses, additive genetic effects accounted for about a quarter (23.64%) of the variance (95%CI 20.17, 27.09%) with the remainder accounted for by non-shared environmental influences. The implications of these findings for handedness both as a primary phenotype and as a covariate in linkage and association analyses are discussed.

Sequence variants in three loci influence monocyte counts and erythrocyte volume

Blood cells participate in vital physiological processes, and their numbers are tightly regulated so that homeostasis is maintained. Disruption of key regulatory mechanisms underlies many blood-related Mendelian diseases but also contributes to more common disorders, including atherosclerosis. We searched for quantitative trait loci (QTL) for hematology traits through a whole-genome association study, because these could provide new insights into both hemopoeitic and disease mechanisms. We tested 1.8 million variants for association with 13 hematology traits measured in 6015 individuals from the Australian and Dutch populations. These traits included hemoglobin composition, platelet counts, and red blood cell and white blood cell indices. We identified three regions of strong association that, to our knowledge, have not been previously reported in the literature. The first was located in an intergenic region of chromosome 9q31 near LPAR1, explaining 1.5% of the variation in monocyte counts (best SNP rs7023923, p=8.9x10(-14)). The second locus was located on chromosome 6p21 and associated with mean cell erythrocyte volume (rs12661667, p=1.2x10(-9), 0.7% variance explained) in a region that spanned five genes, including CCND3, a member of the D-cyclin gene family that is involved in hematopoietic stem cell expansion. The third region was also associated with erythrocyte volume and was located in an intergenic region on chromosome 6q24 (rs592423, p=5.3x10(-9), 0.6% variance explained). All three loci replicated in an independent panel of 1543 individuals (p values=0.001, 9.9x10(-5), and 7x10(-5), respectively). The identification of these QTL provides new opportunities for furthering our understanding of the mechanisms regulating hemopoietic cell fate.

Replication of the association of common rs9939609 variant of FTO with increased BMI in an Australian adult twin population but no evidence for gene by environment (G x E) interaction

OBJECTIVE: To further investigate a common variant (rs9939609) in the fat mass- and obesity-associated gene (FTO), which recent genome-wide association studies have shown to be associated with body mass index (BMI) and obesity. DESIGN: We examined the effect of this FTO variant on BMI in 3353 Australian adult male and female twins. RESULTS: The minor A allele of rs9939609 was associated with an increased BMI (P=0.0007). Each additional copy of the A allele was associated with a mean BMI increase of approximately 1.04 kg/m(2) (approximately 3.71 kg). Using variance components decomposition, we estimate that this single-nucleotide polymorphism accounts for approximately 3% of the genetic variance in BMI in our sample (approximately 2% of the total variance). By comparing intrapair variances of monozygotic twins of different genotypes we were able to perform a direct test of gene by environment (G x E) interaction in both sexes and gene by parity (G x P) interaction in women, but no evidence was found for either. CONCLUSIONS: In addition to supporting earlier findings that the rs9939609 variant in the FTO gene is associated with an increased BMI, our results indicate that the associated genetic effect does not interact with environment or parity.

Quantitative Trait Loci for CD4:CD8 Lymphocyte Ratio Are Associated with Risk of Type 1 Diabetes and HIV-1 Immune Control

Abnormal expansion or depletion of particular lymphocyte subsets is associated with clinical manifestations such as HIV progression to AIDS and autoimmune disease. We sought to identify genetic predictors of lymphocyte levels and reasoned that these may play a role in immune-related diseases. We tested 2.3 million variants for association with five lymphocyte subsets, measured in 2538 individuals from the general population, including CD4+ T cells, CD8+ T cells, CD56+ natural killer (NK) cells, and the derived measure CD4:CD8 ratio. We identified two regions of strong association. The first was located in the major histocompatibility complex (MHC), with multiple SNPs strongly associated with CD4:CD8 ratio (rs2524054, p = 2.1 × 10−28). The second region was centered within a cluster of genes from the Schlafen family and was associated with NK cell levels (rs1838149, p = 6.1 × 10−14). The MHC association with CD4:CD8 replicated convincingly (p = 1.4 × 10−9) in an independent panel of 988 individuals. Conditional analyses indicate that there are two major independent quantitative trait loci (QTL) in the MHC region that regulate CD4:CD8 ratio: one is located in the class I cluster and influences CD8 levels, whereas the second is located in the class II cluster and regulates CD4 levels. Jointly, both QTL explained 8% of the variance in CD4:CD8 ratio. The class I variants are also strongly associated with durable host control of HIV, and class II variants are associated with type-1 diabetes, suggesting that genetic variation at the MHC may predispose one to immune-related diseases partly through disregulation of T cell homeostasis.

Within-family outliers: Segregating alleles or environmental effects? A linkage analysis of height from 5815 sibling pairs

Most information in linkage analysis for quantitative traits comes from pairs of relatives that are phenotypically most discordant or concordant. Confounding this, within-family outliers from non-genetic causes may create false positives and negatives. We investigated the influence of within-family outliers empirically, using one of the largest genome-wide linkage scans for height. The subjects were drawn from Australian twin cohorts consisting of 8447 individuals in 2861 families, providing a total of 5815 possible pairs of siblings in sibships. A variance component linkage analysis was performed, either including or excluding the within-family outliers. Using the entire dataset, the largest LOD scores were on chromosome 15q (LOD 2.3) and 11q (1.5). Excluding within-family outliers increased the LOD score for most regions, but the LOD score on chromosome 15 decreased from 2.3 to 1.2, suggesting that the outliers may create false negatives and false positives, although rare alleles of large effect may also be an explanation. Several regions suggestive of linkage to height were found after removing the outliers, including 1q23.1 (2.0), 3q22.1 (1.9) and 5q32 (2.3). We conclude that the investigation of the effect of within-family outliers, which is usually neglected, should be a standard quality control measure in linkage analysis for complex traits and may reduce the noise for the search of common variants of modest effect size as well as help identify rare variants of large effect and clinical significance. We suggest that the effect of within-family outliers deserves further investigation via theoretical and simulation studies.

Genetic and environmental influences on migraine: a twin study across six countries

Migraine is a common neurovascular brain disorder that is manifested in recurrent episodes of disabling headache. The aim of the present study was to compare the prevalence and heritability of migraine across six of the countries that participate in GenomEUtwin project including a total number of 29,717 twin pairs. Migraine was assessed by questionnaires that differed between most countries. It was most prevalent in Danish and Dutch females (32% and 34%, respectively), whereas the lowest prevalence was found in the younger and older Finnish cohorts (13% and 10%, respectively). The estimated genetic variance (heritability) was significant and the same between sexes in all countries. Heritability ranged from 34% to 57%, with lowest estimates in Australia, and highest estimates in the older cohort of Finland, the Netherlands, and Denmark. There was some indication that part of the genetic variance was non-additive, but this was significant in Sweden only. In addition to genetic factors, environmental effects that are non-shared between members of a twin pair contributed to the liability of migraine. After migraine definitions are homogenized among the participating countries, the GenomEUtwin project will provide a powerful resource to identify the genes involved in migraine.

Association of a low density lipoprotein receptor microsatellite variant with obesity

OBJECTIVE: To determine whether a microsatellite polymorphism located towards the 3' end of the low density lipoprotein receptor gene (LDLR) is associated with obesity. DESIGN: A cross-sectional case-control study. SUBJECTS: One hundred and seven obese individuals, defined as a body mass index (BMI) > or = 26 kg/m2, and 163 lean individuals, defined as a BMI < 26 kg/m2. MEASUREMENTS: BMI, blood pressure, serum lipids, alleles of LDLR microsatellite (106 bp, 108 bp and 112 bp). RESULTS: There was a significant association between variants of the LDLR microsatellite and obesity, in the overall tested population, due to a contributing effect in females (chi 2 = 12.3, P = 0.002), but not in males (chi 2 = 0.3, P = 0.87). In females, individuals with the 106 bp allele were more likely to be lean, while individuals with the 112 bp and/or 108 bp alleles tended to be obese. CONCLUSIONS: These results suggest that in females, LDLR may play a role in the development of obesity.

A flexible hierarchical approach for facial age estimation based on multiple features

Age estimation from facial images is increasingly receiving attention to solve age-based access control, age-adaptive targeted marketing, amongst other applications. Since even humans can be induced in error due to the complex biological processes involved, finding a robust method remains a research challenge today. In this paper, we propose a new framework for the integration of Active Appearance Models (AAM), Local Binary Patterns (LBP), Gabor wavelets (GW) and Local Phase Quantization (LPQ) in order to obtain a highly discriminative feature representation which is able to model shape, appearance, wrinkles and skin spots. In addition, this paper proposes a novel flexible hierarchical age estimation approach consisting of a multi-class Support Vector Machine (SVM) to classify a subject into an age group followed by a Support Vector Regression (SVR) to estimate a specific age. The errors that may happen in the classification step, caused by the hard boundaries between age classes, are compensated in the specific age estimation by a flexible overlapping of the age ranges. The performance of the proposed approach was evaluated on FG-NET Aging and MORPH Album 2 datasets and a mean absolute error (MAE) of 4.50 and 5.86 years was achieved respectively. The robustness of the proposed approach was also evaluated on a merge of both datasets and a MAE of 5.20 years was achieved. Furthermore, we have also compared the age estimation made by humans with the proposed approach and it has shown that the machine outperforms humans. The proposed approach is competitive with current state-of-the-art and it provides an additional robustness to blur, lighting and expression variance brought about by the local phase features.

Evaluation of visual stress symptoms in Age-matched Dyslexic, Meares–Irlen syndrome (MIS) and normal adults

AIM To examine the prevalence of dyslexia and Meares–Irlen syndrome (MIS) among female students and determine their level of visual stress in comparison with normal subjects. METHODS A random sample of 450 female medical students of King Saud University Riyadh (age range, 18 - 30 years) responded to a wide range of questions designed to accomplish the aims of this study. The detailed questionnaire consisted of 54 questions with twelve questions enquiring on ocular history and demography of participants while 42 questions were on visual symptoms. Items were categorized into; critical and non-critical questions (CQ and NCQ) and were rated on four point Likert scale. Based on the responses obtained, the subjects were grouped into normal (control), dyslexic with or without MIS (Group 1) and subjects with MIS only (Group 2). Responses were analysed as averages and mean scores were calculated and compared between-groups using one way analysis of variance to evaluate total (TVSS = NCQ + CQ), critical and non-critical visual stress scores. The relationship between categorical variables such as age, handedness and condition were assessed with Chi- Square test. RESULTS The completion rate was 96.8% and majority of the respondents (92%) were normal readers, 2% dyslexic and 6% had MIS. They were age-matched. More than half of the participants had visited an eye care practitioner in the last 2yrs. About 13% were recommended eye exercises and one participant experienced pattern glare. Hand preference was not associated with any condition but Group 1 subjects (3/9, 33%) were significantly more likely to be diagnosed of lazy eye than Group 2 (2/27, 7%) and control (27/414, 5%) subjects. The mean ± SD of TVSS responses were 63 ± 14 but it was 44 ± 9 for CQ and 19 ± 5 for NCQ. Responses from all three variables were normally distributed but the CQ responses were on the average more positive (82%) in Group 2 and less positive (46%) in Group 1 than control. With NCQ, the responses were equally less positive in Group 1 and 2 than control. Group 2 subjects showed significantly higher TVSS (P = 0.002), NCQ (P = 0.006) and CQ (P = 0.008) visual stress scores than control but no difference between Group 1 and control subjects, was observed for all scores (P > 0.05, for all comparisons). CONCLUSION The prevalence of dyslexia and MIS among Saudi female students was 2 and 6%, respectively. Critical questions performed best for assessing visual stress symptoms in dyslexic and MIS subjects. Generally, students with MIS were more sensitive to visual stress than normal students but dyslexics were more likely to present with a lazy eye than MIS and normal readers.

Lernen im Team: Zusammenhänge zwischen Personen- und Teammerkmalen und der Leistung von Multiplikatoren [Learning in teams: Relationships between individual and team characteristics and the performance of multipliers]

The continuous mutual transfer of knowledge and skills within work teams is increasingly important for organizational practice. According to the situational and experience-based approaches of applied learning research, certain individual and social prerequisites have to be met for successful learning in teams. In a field study at an automobile production site, it was investigated which personal characteristics of multipliers and which characteristics of teams are related to the performance of multipliers in 31 teams with 291 coworkers. Using multi-level analyses (HLM), the amount of variance explained by the predictor variables in teaching success of multipliers and learning success of coworkers was examined. Results showed that multipliers' conscientiousness and team cohesion were related to teaching success of multipliers; extraversion and team cohesion were related to the learning success of coworkers. In closing, the scientific and practical implications for the investigation and promotion of work-based learning processes in teams are discussed.

Reliability and validity of objective measures of physical activity in youth with cerebral palsy who are ambulatory

BACKGROUND Physical therapy for youth with cerebral palsy (CP) who are ambulatory includes interventions to increase functional mobility and participation in physical activity (PA). Thus, reliable and valid measures are needed to document PA in youth with CP. OBJECTIVE The purpose of this study was to evaluate the inter-instrument reliability and concurrent validity of 3 accelerometer-based motion sensors with indirect calorimetry as the criterion for measuring PA intensity in youth with CP. METHODS Fifty-seven youth with CP (mean age=12.5 years, SD=3.3; 51% female; 49.1% with spastic hemiplegia) participated. Inclusion criteria were: aged 6 to 20 years, ambulatory, Gross Motor Function Classification System (GMFCS) levels I through III, able to follow directions, and able to complete the full PA protocol. Protocol activities included standardized activity trials with increasing PA intensity (resting, writing, household chores, active video games, and walking at 3 self-selected speeds), as measured by weight-relative oxygen uptake (in mL/kg/min). During each trial, participants wore bilateral accelerometers on the upper arms, waist/hip, and ankle and a portable indirect calorimeter. Intraclass coefficient correlations (ICCs) were calculated to evaluate inter-instrument reliability (left-to-right accelerometer placement). Spearman correlations were used to examine concurrent validity between accelerometer output (activity and step counts) and indirect calorimetry. Friedman analyses of variance with post hoc pair-wise analyses were conducted to examine the validity of accelerometers to discriminate PA intensity across activity trials. RESULTS All accelerometers exhibited excellent inter-instrument reliability (ICC=.94-.99) and good concurrent validity (rho=.70-.85). All accelerometers discriminated PA intensity across most activity trials. LIMITATIONS This PA protocol consisted of controlled activity trials. CONCLUSIONS Accelerometers provide valid and reliable measures of PA intensity among youth with CP.

Analysing the Impact of Learning Inputs - Application to Terrain Traversability Estimation

Data-driven approaches such as Gaussian Process (GP) regression have been used extensively in recent robotics literature to achieve estimation by learning from experience. To ensure satisfactory performance, in most cases, multiple learning inputs are required. Intuitively, adding new inputs can often contribute to better estimation accuracy, however, it may come at the cost of a new sensor, larger training dataset and/or more complex learning, some- times for limited benefits. Therefore, it is crucial to have a systematic procedure to determine the actual impact each input has on the estimation performance. To address this issue, in this paper we propose to analyse the impact of each input on the estimate using a variance-based sensitivity analysis method. We propose an approach built on Analysis of Variance (ANOVA) decomposition, which can characterise how the prediction changes as one or more of the input changes, and also quantify the prediction uncertainty as attributed from each of the inputs in the framework of dependent inputs. We apply the proposed approach to a terrain-traversability estimation method we proposed in prior work, which is based on multi-task GP regression, and we validate this implementation experimentally using a rover on a Mars-analogue terrain.