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Most genome-wide association (GWA) studies have focused on populations of European ancestry with limited assessment of the influence of the sequence variants on populations of other ethnicities. To determine whether markers that we have recently shown to associate with Bone Mineral Density (BMD) in Europeans also associate with BMD in East-Asians we analysed 50 markers from 23 genomic loci in samples from Korea (n = 1,397) and two Chinese Hong Kong sample sets (n = 3,869 and n = 785). Through this effort we identified fourteen loci that associated with BMD in East-Asian samples using a false discovery rate (FDR) of 0.05; 1p36 (ZBTB40, P = 4.3×10(-9)), 1p31 (GPR177, P = 0.00012), 3p22 (CTNNB1, P = 0.00013), 4q22 (MEPE, P = 0.0026), 5q14 (MEF2C, P = 1.3×10(-5)), 6q25 (ESR1, P = 0.0011), 7p14 (STARD3NL, P = 0.00025), 7q21 (FLJ42280, P = 0.00017), 8q24 (TNFRSF11B, P = 3.4×10(-5)), 11p15 (SOX6, P = 0.00033), 11q13 (LRP5, P = 0.0033), 13q14 (TNFSF11, P = 7.5×10(-5)), 16q24 (FOXL1, P = 0.0010) and 17q21 (SOST, P = 0.015). Our study marks an early effort towards the challenge of cataloguing bone density variants shared by many ethnicities by testing BMD variants that have been established in Europeans, in East-Asians.

Bone mineral density (BMD), a diagnostic parameter for osteoporosis and a clinical predictor of fracture, is a polygenic trait with high heritability. To identify genetic variants that influence BMD in different ethnic groups, we performed a genome-wide association study (GWAS) on 800 unrelated Southern Chinese women with extreme BMD and carried out follow-up replication studies in six independent study populations of European descent and Asian populations including 18,098 subjects. In the meta-analysis, rs2273061 of the Jagged1 (JAG1) gene was associated with high BMD (p = 5.27 x 10(-8) for lumbar spine [LS] and p = 4.15 x 10(-5) for femoral neck [FN], n = 18,898). This SNP was further found to be associated with the low risk of osteoporotic fracture (p = 0.009, OR = 0.7, 95% CI 0.57-0.93, n = 1881). Region-wide and haplotype analysis showed that the strongest association evidence was from the linkage disequilibrium block 5, which included rs2273061 of the JAG1 gene (p = 8.52 x 10(-9) for LS and 3.47 x 10(-5) at FN). To assess the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of c-Myc to the "G" but not "A" allele of rs2273061. A mRNA expression study in both human bone-derived cells and peripheral blood mononuclear cells confirmed association of the high BMD-related allele G of rs2273061 with higher JAG1 expression. Our results identify the JAG1 gene as a candidate for BMD regulation in different ethnic groups, and it is a potential key factor for fracture pathogenesis., (Copyright (c) 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The instability of the CAG repeat size of the HD gene when transmitted intergenerationally has critical implications for genetic counseling practices. In particular, CAG repeats between 27 and 35 have been the subject of debate based on small samples. To address this issue, we analyzed allelic instability in the Venezuelan HD kindreds, the largest and most informative families ascertained for HD. We identified 647 transmissions. Our results indicate that repeats in the 27-35 CAG range are highly stable. Out of 69 transmitted alleles in this range, none expand into any penetrant ranges. Contrastingly, 14% of alleles transmitted from the incompletely penetrant range (36-39 CAGs) expand into the completely penetrant range, characterized by alleles with 40 or more CAG repeats. At least 12 of the 534 transmissions from the completely penetrant range contract into the incompletely penetrant range of 36-39 CAG repeats. In these kindreds, none of the individuals with 27-39 CAGs were symptomatic, even though they ranged in age from 11 to 82 years. We expect these findings to be helpful in updating genetic counseling practices., ((c) 2008 Wiley-Liss, Inc.)

The epidemiology of multiple sclerosis suggests that a complex interaction of genes and environment contribute to susceptibility. To enrich for families with large genetic effects and to potentially reduce genetic heterogeneity, we screened a sample of 18,794 probands and identified forty families with four or more affected individuals. Within these 40 families, HLA DRB1*15 was present in 70% of affected individuals; the transmission disequilibrium test showed a significant excess in transmission of DRB1*15 alleles to affected individuals (47 transmitted, 19 untransmitted, chi (2) = 11.9, p = 0.00057). A 10 cM genome scan was performed and analyzed for linkage under a parametric model with heterogeneity. No excess of significant sharing was observed (HLOD > 3.3) in the parametric multipoint analysis. No region exceeded that for marker GATA8A05 with an HLOD = 1.11. Follow-up genotyping with 17 microsatellites revealed a significant two-point parametric HLOD = 3.99 at marker D4S1597. Transmission disequilibrium tests for markers in this candidate region showed no transmission distortion. A scan for variants in a gene adjacent to D4S1597, PALLD, was negative for synonymous or nonsynonymous changes. A final multipoint scan incorporating all microsatellites in the region provided an HLOD = 1.30. The inability to find significant linkage in these highly penetrant families suggests that linkage is not the optimal tool for dissecting the inheritance of MS.

Strong evidence of linkage to late-onset Alzheimer disease (LOAD) has been observed on chromosome 10, which implicates a wide region and at least one disease-susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial. We performed a chromosome 10-specific association study with 1,412 gene-based single-nucleotide polymorphisms (SNPs), to identify susceptibility genes for developing LOAD. The scan included SNPs in 677 of 1,270 known or predicted genes; each gene contained one or more markers, about half (48%) of which represented putative functional mutations. In general, the initial testing was performed in a white case-control sample from the St. Louis area, with 419 LOAD cases and 377 age-matched controls. Markers that showed significant association in the exploratory analysis were followed up in several other white case-control sample sets to confirm the initial association. Of the 1,397 markers tested in the exploratory sample, 69 reached significance (P < .05). Five of these markers replicated at P < .05 in the validation sample sets. One marker, rs498055, located in a gene homologous to RPS3A (LOC439999), was significantly associated with Alzheimer disease in four of six case-control series, with an allelic P value of .0001 for a meta-analysis of all six samples. One of the case-control samples with significant association to rs498055 was derived from the linkage sample (P = .0165). These results indicate that variants in the RPS3A homologue are associated with LOAD and implicate this gene, adjacent genes, or other functional variants (e.g., noncoding RNAs) in the pathogenesis of this disorder.

Background: Erythroderma, defined as red skin covering most of the body surface often accompanied or followed by exfoliation, is the clinical manifestation of at least six different underlying etiologies with allergic or irritant contact dermatitis, atopic/asteotic dermatitis, pityriasis rubra pilaris (PRP), psoriasis, and seborrheic dermatitis accounting for the majority of cases. Approximately 10% of cases are due to adverse drug reactions with roughly another 10% due to cutaneous T-cell lymphoma (CTCL), predominantly mycosis fungoides, or leukemia. It is clear from multiple studies that the clinical diagnosis of the underlying entity is often difficult, as these diseases can present in a very similar fashion. A skin biopsy is usually employed in this setting as a diagnostic tool. However, the histopathologic diagnosis of the underlying cause is complicated by the subtlety of the distinguishing histologic features. In this situation, an ancillary technique demonstrating the presence of a monoclonal T-cell proliferation could help to rule in or out CTCL in cases that clinically and histopathologically do not allow a definitive diagnosis., Methods: We retrospectively studied 25 biopsies from sixteen patients who presented to the Stanford Dermatology Clinic with erythroderma. We examined the specimens morphologically and analyzed the gamma chain of the T-cell receptor (TCR- gamma) by polymerase chain reaction (PCR) followed by heteroduplex analysis for clonality. We then correlated the results of our PCR and heteroduplex analyses with the patients' clinical outcomes., Results: Four biopsies, from three patients, contained clonal TCR-gamma rearrangements; the four biopsies, all of which were equivocal histologically, correlated to diagnoses of mycosis fungoides (MF) or Sézary syndrome (SS). Twenty-one biopsies contained polyclonal T-cell populations. Eighteen of these biopsies represent patients with inflammatory dermatoses. Three of these biopsies, all of which were taken from a single patient, correlate to a diagnosis of MF., Conclusion: TCR-gamma PCR heteroduplex analysis seems to represent an important adjuvant diagnostic tool that, used in conjunction with histopathology and clinical history, could help to clarify the underlying etiology of erythroderma.

Dense maps of short-tandem-repeat polymorphisms (STRPs) have allowed genome-wide searches for genes involved in a great variety of diseases with genetic influences, including common complex diseases. Generally for this purpose, marker sets with a 10 cM spacing are genotyped in hundreds of individuals. We have performed power simulations to estimate the maximum possible intermarker distance that still allows for sufficient power. In this paper we further report on modifications of previously published protocols, resulting in a powerful screening set containing 229 STRPs with an average spacing of 18.3 cM. A complete genome scan using our protocol requires only 80 multiplex PCR reactions which are all carried out using one set of conditions and which do not contain overlapping marker allele sizes. The multiplex PCR reactions are grouped by sets of chromosomes, which enables on-line statistical analysis of a set of chromosomes, as sets of chromosomes are being genotyped. A genome scan following this modified protocol can be performed using a maximum amount of 2.5 micrograms of genomic DNA per individual, isolated from either blood or from mouth swabs.

Errors in genotyping can substantially influence the power to detect linkage using affected sib-pairs, but it is not clear what effect such errors have on quantitative trait analyses. Here we use Monte Carlo simulation to examine the influence of genotyping error on multipoint vs two-point analysis, variable map density, locus effect size and allele frequency in quantitative trait linkage and association studies of sib-pairs. The analyses are conducted using variance components methods. We contrast the effects of error on quantitative trait analyses with those on the affected sib-pair design. The results indicate that genotyping error influences linkage studies of affected sib pairs more severely than studies of quantitative traits in unselected sibs. In situations of modest effect size, 5% genotyping error eliminates all supporting evidence for linkage to a true susceptibility locus in affected pairs, but may only result in a loss of 15% of linkage information in random pairs. Multipoint analysis does not suffer substantially more than two-point analysis; for moderate error rates (< 5%), multipoint analysis with error is more powerful than two-point with no error. Map density does not appear to be an important factor for linkage analysis. QTL association analyses of common alleles are reasonably robust to genotyping error but power can be affected dramatically with rare alleles.

The effects of genotype and relationship errors on linkage results are evaluated in three of the Genetic Analysis Workshop 12 asthma genome scans. A number of errors are detected in the samples. While the evidence for linkage is not striking in any data set with or without error, in some cases the difference in test statistic could support different conclusions. The results provide empirical evidence for the predicted effects of genotype and relationship error and highlight the need for rigorous detection and elimination of data error in complex trait studies.

Association analyses conducted in a variance components framework can include information from all available individuals but remain unbiased in the presence of familiality or linkage. Models that include both linkage and association parameters provide different estimates of the effect of a single locus and can be used to distinguish causal polymorphisms from other types of variation. We examine some of these models and their properties in a blind analysis of the simulated Genetic Analysis Workshop 12 data sets.

There is considerable evidence for a unitary and dimensional view of the genetic vulnerability to symptoms of anxiety and depression. The GENESiS (Genetic Environmental-Nature of Emotional States in Siblings) Study aims to use a multivariate approach to detect genetic loci that contribute to individual differences in this vulnerability dimension. The study used the UK General Practice Research Framework to generate a community-based sample of siblings. Questionnaire measures of anxiety/depression included the short form of the neuroticism scale from the revised Eysenck Personality Questionnaire (EPQ-N), the General Health Questionnaire (GHQ-12), and the anxious arousal and high positive affect subscales from the Mood and Anxiety Symptoms Questionnaire (MASQ-AA and MASQ-HPA). Genetic model-fitting of 2658 unselected sibships provided evidence for a single common genetic (familial) factor that accounted for a substantial proportion of the genetic variances and covariances of these four measures. Using the parameter estimates of this model, we constructed a composite index of this common genetic factor. This index, which has a sib correlation of 0.22, will be used as a quantitative phenotype in the molecular genetic phase of GENESiS.

Twin studies of child temperament using objective measures consistently suggest moderate heritability for most dimensions. However, parent rating measures produce unusual patterns of results. Intraclass correlations for identical (MZ) twins are typically high, whereas fraternal (DZ) twin intraclass correlations are much lower than would be predicted from an additive genetic model. The 'too low' DZ correlations can be explained by parent-rating biases that either exaggerate the differences between DZ twins (contrast effects) or that inflate the similarity of MZ twins (assimilation effects), or by the presence of non-additive genetic variance. To evaluate the three possible explanations, we used model-fitting procedures applied to parent-rating data averaged across 14, 20, 24, and 36 months of age in a sample of 196 twin pairs participating in the MacArthur Longitudinal Twin Study. The data were best described by a model that included contrast effects. Implications for non-twin research are discussed.

Standard variance-components quantitative trait loci (QTL) linkage analysis can produce an elevated rate of type 1 errors when applied to selected samples and non-normal data. Here we describe an adjustment of the log-likelihood function based on conditioning on trait values. This leads to a likelihood ratio test that is valid in selected samples and non-normal data, and equal in power to alternative methods for analyzing selected samples that require knowledge of the ascertainment procedure or the trait values of non-selected individuals.

Screening the whole genome of a cross between two inbred animal strains has proved to be a powerful method for detecting genetic loci underlying quantitative behavioural traits, but the level of resolution offered by quantitative trait loci (QTL) mapping is still too coarse to permit molecular cloning of the genetic determinants. To achieve high-resolution mapping, we used an outbred stock of mice for which the entire genealogy is known. The heterogeneous stock (HS) was established 30 years ago from an eight-way cross of C57BL/6, BALB/c, RIII, AKR, DBA/2, I, A/J and C3H inbred mouse strains. At the time of the experiment reported here, the HS mice were at generation 58, theoretically offering at least a 30-fold increase in resolution for QTL mapping compared with a backcross or an F2 intercross. Using the HS mice we have mapped a QTL influencing a psychological trait in mice to a 0.8-cM interval on chromosome 1. This method allows simultaneous fine mapping of multiple QTLs, as shown by our report of a second QTL on chromosome 12. The high resolution possible with this approach makes QTLs accessible to positional cloning.

Reading disability (RD), or dyslexia, is a complex cognitive disorder manifested by difficulties in learning to read, in otherwise normal individuals. Individuals with RD manifest deficits in several reading and language skills. Previous research has suggested the existence of a quantitative-trait locus (QTL) for RD on the short arm of chromosome 6. In the present study, RD subjects' performance in several measures of word recognition and component skills of orthographic coding, phonological decoding, and phoneme awareness were individually subjected to QTL analysis, with a new sample of 126 sib pairs, by means of a multipoint mapping method and eight informative DNA markers on chromosome 6 (D6S461, D6S276, D6S105, D6S306, D6S258, D6S439, D6S291, and D6S1019). The results indicate significant linkage across a distance of at least 5 cM for deficits in orthographic (LOD = 3.10) and phonological (LOD = 2.42) skills, confirming previous findings.

An extension to current maximum-likelihood variance-components procedures for mapping quantitative-trait loci in sib pairs that allows a simultaneous test of allelic association is proposed. The method involves modeling of the allelic means for a test of association, with simultaneous modeling of the sib-pair covariance structure for a test of linkage. By partitioning of the mean effect of a locus into between- and within-sibship components, the method controls for spurious associations due to population stratification and admixture. The power and efficacy of the method are illustrated through simulation of various models of both real and spurious association.

Power to detect genetic and environmental influences increases not only with sample size but also with the number of measurements through longitudinal and/or multivariate designs, if those measurements correlate with each other. Power simulations are presented for uni- through quadrivariate cases, with differing genetic and environmental parameters. Even though subject attrition is a problem for most longitudinal studies, the gain in power available may more than make up for this shortcoming in many situations. In terms of planning studies to examine genetic and environmental influences, power calculations should not only consider sample size but number of measurements on particular phenotypes and their intercorrelations.

Although numerous theories have attempted to explain the origins of high general cognitive ability (g), the genetic and environmental etiology of high g during infancy and early childhood has not previously been investigated. We report results of a twin study of high cognitive ability at 14, 20, 24, and 36 months using twins from the more than 600 children participating in the MacArthur Longitudinal Twin Study. High g groups were formed from the ninetieth percentile and above at each age, with IQ equivalent means at or above 126 across the ages. Results suggest increasing genetic influence and increasing genetic stability from 14 to 36 months using DeFries-Fulker multiple regression analyses. However, genetic influences are substantial when examining individuals who possess high g scores averaged across all 4 ages. These results suggest that, although high cognitive ability may be genetically influenced in early childhood, these influences differ in magnitude from 14 to 36 months.

The genetic and environmental etiology of low general cognitive ability (g) during infancy and early childhood has not previously been investigated. The current study examined the genetic etiology of low cognitive ability at 14, 20, 24, and 36 months with twins from the MacArthur Longitudinal Twin Study. Low g groups were formed from the lowest 10th percentile at each age. Univariate probandwise concordance rates and DeFries-Fulker (J. C. DeFries & D. W. Fulker, 1985, 1988) multiple regression techniques suggest genetic etiology in low general cognitive ability groups. The stability of low general cognitive ability over time also appears to be primarily due to genetic factors. Although replication is necessary, these results suggest that the genetic etiology of low g during infancy and early childhood is at least as great as the heritability of g in the unselected population.

This study describes results from an ongoing family study of adolescent boys and their families designed to investigate potential risk factors for substance abuse. The adolescent treatment probands have severe drug and alcohol related problems and were recruited through a residential rehabilitation program. To date, the sample includes 251 individuals: 39 male probands and their families and 34 control families matched for age and geographic location (zip code). Probands and participating family members are given a structured interview which assesses alcohol and drug problems, and various psychiatric symptoms. The purpose of the present study was to examine the coaggregation of depressive symptoms, antisocial behavior, and alcohol misuse. Multivariate pedigree analyses were performed using a model that allowed for the estimation of vertical familial transmission, residual sibling resemblance, and assortative mating. Spouse correlations were estimated at .57, .21, and .31 for antisocial behavior, depressive symptoms, and alcohol abuse, respectively. Residual sibling environment (i.e., sibling resemblance unaccounted for by parent-offspring transmission) was not found for alcohol problem symptoms, but did contribute to resemblance for antisocial behavior and depressive symptoms. The proportion of variance accounted for by vertical familial transmission was estimated at approximately 30 to 40%. More important, correlations among the transmissible family factors for these psychiatric syndromes ranged from .58 to .73, suggesting substantial overlap among the underlying familial antecedents for these disorders.

We have extended our analysis of the role of the long arm of the X chromosome (Xq28) in sexual orientation by DNA linkage analyses of two newly ascertained series of families that contained either two gay brothers or two lesbian sisters as well as heterosexual siblings. Linkage between the Xq28 markers and sexual orientation was detected for the gay male families but not for the lesbian families or for families that failed to meet defined inclusion criteria for the study of sex-linked sexual orientation. Our results corroborate the previously reported linkage between Xq28 and male homosexuality in selected kinships and suggest that this region contains a locus that influences individual variations in sexual orientation in men but not in women.

The sib-pair interval-mapping procedure of Fulker and Cardon is extended to take account of all available marker information on a chromosome simultaneously. The method provides a computationally fast multipoint analysis of sib-pair data, using a modified Haseman-Elston approach. It gives results very similar to those of the earlier interval-mapping procedure when marker information is relatively uniform and a coarse map is used. However, there is a substantial improvement over the original method when markers differ in information content and/or when a dense map is employed. The method is illustrated by using simulated sib-pair data.

Sib pairs drawn from the simulated common oligogenic disease families were selected for extreme quantitative trait scores and analyzed using interval mapping and multipoint methods. Linkage analyses of 112 selected sib pairs, in which one or more members had trait values exceeding the disease threshold, were compared with analyses of the total unselected sib-pair sample (771 pairs). Selected sample regression models yielded comparable significance levels to those obtained from the unselected sample at most loci on the six simulated chromosomes, demonstrating the efficiency of selected sib-pair analysis for quantitative characters. Two of the three disease QTLs were detected in both selected and unselected samples. Interval mapping and multipoint analyses yielded location estimates close to the simulated positions of the QTLs. The combined strategy of using interval mapping and multipoint methods with selected sib pairs appears to provide improved accuracy and sensitivity over more traditional sib-pair methods for detecting quantitative trait loci.

Items in various scales that measure socially desirable responding (SDR) appear to vary in significance in male and female respondents. Recent findings suggest that females are more sensitive to the contents of more than two-thirds of such items. As a result, scales that measure SDR cannot be considered gender balanced, not to mention gender free. We examined three levels at which SDR items can be construed as gender controlled and arrived at a formula for item selection in the development of gender-controlled scales. Application of the formula resulted in the 10-item Gender-Free Inventory of Desirable Responding (GFIDR), with an inter-item reliability of .68, and the 12-item Gender Balanced Inventory of Desirable Responding (GBIDR), with an inter-item reliability of .71. The distribution characteristics of the two scales suggested that gender differences in the higher moments should be considered in the interpretation of results based on otherwise gender-controlled scales.