How to estimate the measurement error variance associated with ancestry proportion estimates

To show how the variance of the measurement error (ME) associated with individual ancestry proportion estimates can be estimated, especially when the number of ancestral populations (k) is greater than 2. We extend existing internal consistency measures to estimate the ME variance, and we compare these estimates with the ME variance estimated by use of the repeated measurement (RM) approach. Both approaches work by dividing the genotyped markers into subsets. We examine the effect of the number of subsets and of the allocation of markers to each subset on the performance of each approach. We used simulated data for all comparisons. Independently of the value of k, the measures of internal reliability provided less biased and more precise estimates of the ME variance than did those obtained with the RM approach. Both methods tend to perform better when a large number of subsets of markers with similar sizes are considered. Our results will facilitate the use of ME correction methods to address the ME problem in individual ancestry proportion estimates. Our method will improve the ability to control for type I error inflation and loss of power in association tests and other genomic research involving ancestry estimates

A unified framework for multi-locus association analysis of both common and rare variants

<p>Abstract</p> <p>Background</p> <p>Common, complex diseases are hypothesized to result from a combination of common and rare genetic variants. We developed a unified framework for the joint association testing of both types of variants. Within the framework, we developed a union-intersection test suitable for genome-wide analysis of single nucleotide polymorphisms (SNPs), candidate gene data, as well as medical sequencing data. The union-intersection test is a composite test of association of genotype frequencies and differential correlation among markers.</p> <p>Results</p> <p>We demonstrated by computer simulation that the false positive error rate was controlled at the expected level. We also demonstrated scenarios in which the multi-locus test was more powerful than traditional single marker analysis. To illustrate use of the union-intersection test with real data, we analyzed a publically available data set of 319,813 autosomal SNPs genotyped for 938 cases of Parkinson disease and 863 neurologically normal controls for which no genome-wide significant results were found by traditional single marker analysis. We also analyzed an independent follow-up sample of 183 cases and 248 controls for replication.</p> <p>Conclusions</p> <p>We identified a single risk haplotype with a directionally consistent effect in both samples in the gene <it>GAK</it>, which is involved in clathrin-mediated membrane trafficking. We also found suggestive evidence that directionally inconsistent marginal effects from single marker analysis appeared to result from risk being driven by different haplotypes in the two samples for the genes <it>SYN3 </it>and <it>NGLY1</it>, which are involved in neurotransmitter release and proteasomal degradation, respectively. These results illustrate the utility of our unified framework for genome-wide association analysis of common, complex diseases.</p

The Nuclear Transcription Factor PKNOX2 Is a Candidate Gene for Substance Dependence in European-Origin Women

Substance dependence or addiction is a complex environmental and genetic disorder that results in serious health and socio-economic consequences. Multiple substance dependence categories together, rather than any one individual addiction outcome, may explain the genetic variability of such disorder. In our study, we defined a composite substance dependence phenotype derived from six individual diagnoses: addiction to nicotine, alcohol, marijuana, cocaine, opiates or other drugs as a whole. Using data from several genomewide case-control studies, we identified a strong (Odds ratio  = 1.77) and significant (p-value = 7E-8) association signal with a novel gene, PBX/knotted 1 homeobox 2 (PKNOX2), on chromosome 11 with the composite phenotype in European-origin women. The association signal is not as significant when individual outcomes for addiction are considered, or in males or African-origin population. Our findings underscore the importance of considering multiple addiction types and the importance of considering population and gender stratification when analyzing data with heterogeneous population

An African Ancestry-Specific Allele of CTLA4 Confers Protection against Rheumatoid Arthritis in African Americans

Cytotoxic T-lymphocyte associated protein 4 (CTLA4) is a negative regulator of T-cell proliferation. Polymorphisms in CTLA4 have been inconsistently associated with susceptibility to rheumatoid arthritis (RA) in populations of European ancestry but have not been examined in African Americans. The prevalence of RA in most populations of European and Asian ancestry is ∼1.0%; RA is purportedly less common in black Africans, with little known about its prevalence in African Americans. We sought to determine if CTLA4 polymorphisms are associated with RA in African Americans. We performed a 2-stage analysis of 12 haplotype tagging single nucleotide polymorphisms (SNPs) across CTLA4 in a total of 505 African American RA patients and 712 African American controls using Illumina and TaqMan platforms. The minor allele (G) of the rs231778 SNP was 0.054 in RA patients, compared to 0.209 in controls (4.462×10−26, Fisher's exact). The presence of the G allele was associated with a substantially reduced odds ratio (OR) of having RA (AG+GG genotypes vs. AA genotype, OR 0.19, 95% CI: 0.13–0.26, p = 2.4×10−28, Fisher's exact), suggesting a protective effect. This SNP is polymorphic in the African population (minor allele frequency [MAF] 0.09 in the Yoruba population), but is very rare in other groups (MAF = 0.002 in 530 Caucasians genotyped for this study). Markers associated with RA in populations of European ancestry (rs3087243 [+60C/T] and rs231775 [+49A/G]) were not replicated in African Americans. We found no confounding of association for rs231778 after stratifying for the HLA-DRB1 shared epitope, presence of anti-cyclic citrullinated peptide antibody, or degree of admixture from the European population. An African ancestry-specific genetic variant of CTLA4 appears to be associated with protection from RA in African Americans. This finding may explain, in part, the relatively low prevalence of RA in black African populations

Waist circumference percentiles in nationally representative samples of African-American, European-American, and Mexican-American children and adolescents.

OBJECTIVE: To describe and provide estimates of the distribution of waist circumference (WC) according to percentiles in African-, European-, and Mexican-American children, and to test for group differences at different percentiles. STUDY DESIGN: Cross-sectional data from the Third National Health and Nutrition Examination Survey (NHANES III) were examined. The sample evaluated included 9713 nonpregnant persons 2 to 18 years of age with measured values of WCs. Age-, sex-, and ethnicity-specific percentiles were estimated via percentile regression. RESULTS: WC measurements increased in a monotonic fashion across ages but at nonconstant rates and in a manner that varied across age and sex. At higher percentiles of the distribution, estimates of WC differ between Mexican-American (MA) and European-American (EA) and between African-American (AA) and European-American (EA), and, in some cases, exceeded the adult cutoff value for obesity-related disease risk at as early as 13 years of age. CONCLUSION: Age-, sex-, and ethnicity-specific WC percentiles are available for US children and adolescents and can be used as an assessment tool that could impact public health recommendations. Results suggest concern with respect to high WC values among certain ethnic groups

Putative contributors to the secular increase in obesity: exploring the roads less traveled.

OBJECTIVE: To investigate plausible contributors to the obesity epidemic beyond the two most commonly suggested factors, reduced physical activity and food marketing practices. DESIGN: A narrative review of data and published materials that provide evidence of the role of additional putative factors in contributing to the increasing prevalence of obesity. DATA: Information was drawn from ecological and epidemiological studies of humans, animal studies and studies addressing physiological mechanisms, when available. RESULTS: For at least 10 putative additional explanations for the increased prevalence of obesity over the recent decades, we found supportive (although not conclusive) evidence that in many cases is as compelling as the evidence for more commonly discussed putative explanations. CONCLUSION: Undue attention has been devoted to reduced physical activity and food marketing practices as postulated causes for increases in the prevalence of obesity, leading to neglect of other plausible mechanisms and well-intentioned, but potentially ill-founded proposals for reducing obesity rate