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In an attempt to discover and unravel genetic predisposition to complex traits, new statistical methods have emerged that utilize multiple sources of data. This appeal to data aggregation is seen on various levels: across genetic variants, across genomic/biological/environmental measures and across different studies, often with fundamentally differing designs. While combining data can increase power to detect genetic variants associated with disease phenotypes, care must be taken in the design, analysis, and interpretation of such studies. Here, we explore methodologies employed to combine sources of genetic data and discuss the prospects for novel advances in the fields of statistical genetics and genetic epidemiology.

The present study investigated the association between variants in the vitamin D receptor gene (VDR) and protein tyrosine phosphatase, non-receptor type 2 gene (PTPN2), as well as an interaction between VDR and PTPN2 and the risk of islet autoimmunity (IA) and progression to type 1 diabetes (T1D). The Diabetes Autoimmunity Study in the Young (DAISY) has followed children at increased risk of T1D since 1993. Of the 1692 DAISY children genotyped for VDR rs1544410, VDR rs2228570, VDR rs11568820, PTPN2 rs1893217, and PTPN2 rs478582, 111 developed IA, defined as positivity for GAD, insulin or IA-2 autoantibodies on 2 or more consecutive visits, and 38 IA positive children progressed to T1D. Proportional hazards regression analyses were conducted. There was no association between IA development and any of the gene variants, nor was there evidence of a VDR*PTPN2 interaction. Progression to T1D in IA positive children was associated with the VDR rs2228570 GG genotype (HR: 0.49, 95% CI: 0.26-0.92) and there was an interaction between VDR rs1544410 and PTPN2 rs1893217 (p(interaction)=0.02). In children with the PTPN2 rs1893217 AA genotype, the VDR rs1544410 AA/AG genotype was associated with a decreased risk of T1D (HR: 0.24, 95% CI: 0.11-0.53, p=0.0004), while in children with the PTPN2 rs1893217 GG/GA genotype, the VDR rs1544410 AA/AG genotype was not associated with T1D (HR: 1.32, 95% CI: 0.43-4.06, p=0.62). These findings should be replicated in larger cohorts for confirmation. The interaction between VDR and PTPN2 polymorphisms in the risk of progression to T1D offers insight concerning the role of vitamin D in the etiology of T1D., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

DUF1220 domains show the largest human-lineage-specific increase in copy number of any protein-coding region in the human genome and map primarily to 1q21, where deletions and reciprocal duplications have been associated with microcephaly and macrocephaly, respectively. Given these findings and the high correlation between DUF1220 copy number and brain size across primate lineages (R(2) = 0.98; p = 1.8 × 10(-6)), DUF1220 sequences represent plausible candidates for underlying 1q21-associated brain-size pathologies. To investigate this possibility, we used specialized bioinformatics tools developed for scoring highly duplicated DUF1220 sequences to implement targeted 1q21 array comparative genomic hybridization on individuals (n = 42) with 1q21-associated microcephaly and macrocephaly. We show that of all the 1q21 genes examined (n = 53), DUF1220 copy number shows the strongest association with brain size among individuals with 1q21-associated microcephaly, particularly with respect to the three evolutionarily conserved DUF1220 clades CON1(p = 0.0079), CON2 (p = 0.0134), and CON3 (p = 0.0116). Interestingly, all 1q21 DUF1220-encoding genes belonging to the NBPF family show significant correlations with frontal-occipital-circumference Z scores in the deletion group. In a similar survey of a nondisease population, we show that DUF1220 copy number exhibits the strongest correlation with brain gray-matter volume (CON1, p = 0.0246; and CON2, p = 0.0334). Notably, only DUF1220 sequences are consistently significant in both disease and nondisease populations. Taken together, these data strongly implicate the loss of DUF1220 copy number in the etiology of 1q21-associated microcephaly and support the view that DUF1220 domains function as general effectors of evolutionary, pathological, and normal variation in brain size., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the pattern and distribution of nonsyndromic orofacial clefts among patients in the Rift Valley region of northwestern Kenya., Methods: Subjects were categorized anatomically for occurrence of an atypical cleft lip variant (ACL), typical cleft lip (CL), cleft lip and palate (CLP), or cleft palate (CP), and family history of orofacial clefts. Tribal ethnicity data were obtained from both cleft and noncleft clinic attendees., Results: There were 194 patients with CL (52.7%), 153 with CLP (41.6%), and 21 with CP (5.7%). CL constitutes a greater fraction of orofacial clefts in the Rift Valley region than reported elsewhere in Africa, principally due to frequent occurrence of ACL (52.5% of all CL). Among noncleft clinic attendees there was a lower fraction of Bantu and larger fraction of Nilotic-Paranilotic tribal ethnicity than in Kenya overall. In contrast, among patients with orofacial clefts there was significant underrepresentation of Bantu and overrepresentation of Nilotic-Paranilotic tribes, particularly Kalenjin. Patients of Kalenjin origin had a much higher rate of positive family history of orofacial clefts than Bantu patients., Conclusions: There is an unusual anatomic distribution of orofacial clefts in the Kenya Rift Valley, with frequent occurrence of an atypical CL variant. Our findings indicate that Bantu tribes have lower risk of orofacial clefts than Nilotic-Paranilotic tribes, possibly due to inherited genetic differences, perhaps accounting for the relatively low prevalence of orofacial clefts through much of Africa.

Background: Beryllium stimulates TNF-alpha from chronic beryllium disease (CBD) bronchoalveolar lavage (BAL) cells., Objective: We sought to relate TNF polymorphisms to beryllium-stimulated TNF-alpha production, to the development of CBD, and to the risk of more severe CBD over time., Methods: We recruited 147 patients with CBD, 112 beryllium-sensitized subjects, and 323 control subjects; genotyped 5 TNF promoter polymorphisms; and measured beryllium-stimulated and unstimulated BAL cell TNF-alpha production from a subset of subjects., Results: Beryllium-stimulated, but not beryllium-unstimulated, BAL cell TNF-alpha production was significantly increased in patients with CBD compared with that seen in those only sensitized (P = .0002). Those subjects with the TNF -857T allele and the only haplotype (haplotype 4) containing this allele demonstrated significantly lower unstimulated BAL cell TNF-alpha production compared with that seen in noncarriers (P = .009). Patients with CBD alone and combined with sensitized subjects carrying the TNF haplotype 1 compared with those without this haplotype had significantly increased beryllium-stimulated BAL cell TNF-alpha levels (P = .02). We found no significant association between patients with CBD, sensitized subjects, and control subjects with any of the TNF promoter polymorphisms or haplotypes. A greater decrease in Pao(2) at maximum exercise was noted in patients with CBD with the -1031C allele (P = .03) and with haplotypes other than the TNF haplotype 1 (P = .01), 3 (from 5) of which contain the -1031C allele., Conclusions: The -857T allele and haplotype 1 are associated with BAL cell TNF-alpha production, indicating a potential role of TNF promoter variants in regulation of TNF production in sensitized subjects and patients with CBD., Clinical Implications: TNF promoter variants are not risk factors for CBD or sensitization.

Type 2 diabetes mellitus is a complex disorder encompassing multiple metabolic defects. We report results from an autosomal genome scan for type 2 diabetes-related quantitative traits in 580 Finnish families ascertained for an affected sibling pair and analyzed by the variance components-based quantitative-trait locus (QTL) linkage approach. We analyzed diabetic and nondiabetic subjects separately, because of the possible impact of disease on the traits of interest. In diabetic individuals, our strongest results were observed on chromosomes 3 (fasting C-peptide/glucose: maximum LOD score [MLS] = 3.13 at 53.0 cM) and 13 (body-mass index: MLS = 3.28 at 5.0 cM). In nondiabetic individuals, the strongest results were observed on chromosomes 10 (acute insulin response: MLS = 3.11 at 21.0 cM), 13 (2-h insulin: MLS = 2.86 at 65.5 cM), and 17 (fasting insulin/glucose ratio: MLS = 3.20 at 9.0 cM). In several cases, there was evidence for overlapping signals between diabetic and nondiabetic individuals; therefore we performed joint analyses. In these joint analyses, we observed strong signals for chromosomes 3 (body-mass index: MLS = 3.43 at 59.5 cM), 17 (empirical insulin-resistance index: MLS = 3.61 at 0.0 cM), and 19 (empirical insulin-resistance index: MLS = 2.80 at 74.5 cM). Integrating genome-scan results from the companion article by Ghosh et al., we identify several regions that may harbor susceptibility genes for type 2 diabetes in the Finnish population.

This study describes the symptom experience of 570 older women with heart disease and evaluates a disease-management program's impact on symptoms over time. Women were randomly assigned to either usual care or a 4-week program ("Women take PRIDE") designed to improve self-regulation skills by focusing on increasing physical activity. At 4 months follow-up, program women, compared to controls, reported fewer total symptoms (p = 0.01) and decreased symptom frequency (p = 0.02) and bothersomeness (p = 0.02). By 12 months, positive intervention effects emerged within the common cardiac and sleep and rest symptom categories. Program group women reported more improvements in symptoms likely to be affected by increasing physical activity at both follow-ups (p < 0.05).