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Objective: Latent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype., Research Design and Methods: We performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects ( n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes ( n = 2,454 vs. 968) and type 2 diabetes ( n = 2,779 vs. 10,396)., Results: The leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3 , encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes., Conclusions: Our results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies., (© 2018 by the American Diabetes Association.)

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Previous large-scale genome-wide association studies in adult populations have implicated ∽100 loci in determining high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, or triglyceride levels. However, whether these loci also contribute to variations of lipid traits in pediatric populations remain unknown. Here we assayed a population of Philadelphia children by high-density single nucleotide polymorphism arrays, and performed association analysis on lipid traits ascertained from lipid measurements stored in electronic medical records. We examined previously reported lipid trait associations, and found that most of them show identical direction of association in our pediatric cohorts, including genome-wide significant association on cholesteryl ester transfer protein with HDL-C levels (rs3764261, P = 2.1 × 10(-8)) and other significant associations on oxysterol-binding protein-like protein 7, low-density lipoprotein receptor-related protein 4 and low-density lipoprotein receptor-related protein 1. Additionally, we identified suggestive association on low-density lipoprotein receptor-related protein 1B with HDL-C levels (rs17736712, P = 2.1 × 10(-7)), but this signal is not supported by previous meta-analysis on adult cohorts. Finally, we examined rare copy number variants and identified deletions encompassing tetratricopeptide repeat domain 39B in two children with extreme lipid measures. Our results highlight the commonalities and differences of genetic components in determining lipid traits in pediatric versus adult populations. Furthermore, our study demonstrates the unique utility of automated information retrieval from electronic medical records in facilitating the identification of genotype-phenotype associations.

To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 × 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height, their effects on infant head circumference were largely independent of height (P = 3.8 × 10(-7) for rs7980687 and P = 1.3 × 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume, Parkinson's disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.

Recently an association was demonstrated between the single nucleotide polymorphism (SNP), rs10516487, within the B-cell gene BANK1 and systemic lupus erythematosus (SLE) as a consequence of a genome wide association study of this disease in European and Argentinean populations. In a bid for replication, we examined the effects of the R61H non-synonymous variant with respect to SLE in our genotyped American cohorts of European and African ancestry. Utilizing data from our ongoing genome-wide association study in our cohort of 178 Caucasian SLE cases and 1808 Caucasian population-based controls plus 148 African American (AA) SLE cases and 1894 AA population-based controls we investigated the association of the previously described non-synonymous SNP at the BANK1 locus with the disease in the two ethnicities separately. Using a Fisher's exact test, the minor allele frequency (MAF) of rs10516487 in the Caucasian cases was 22.6% while it was 31.2% in Caucasian controls, yielding a protective odds ratio (OR) of 0.64 (95% CI 0.49-0.85; one-sided p = 7.07 × 10(-4)). Furthermore, the MAF of rs10516487 in the AA cases was 18.7% while it was 23.3% in AA controls, yielding a protective OR of 0.75 (95% CI 0.55-1.034; one-sided p = 0.039). The OR of the BANK1 variant in our study cohorts is highly comparable with that reported previously in a South American/European SLE case-control cohort (OR = 0.72). As such, R61H in the BANK1 gene confers a similar magnitude of SLE protection, not only in European Americans, but also in African Americans.