Historical and genetic evidences suggest that the recently founded population of Antioquia (Colombia) is potentially useful for the genetic mapping of complex traits. This population was established in the 16th-17th centuries through the admixture of Amerinds, Europeans, and Africans and grew in relative isolation until the late 19th century. To examine the origin of the founders of Antioquia, we typed 11 markers on the nonrecombining portion of the Y chromosome and four markers on mtDNA in a sample of individuals with confirmed Antioquian ancestry. The polymorphisms on the Y chromosome (five biallelic markers and six microsatellites) allow an approximation to the origin of founder men, and those on mtDNA identify the four major founder Native American lineages. These data indicate that approximately 94% of the Y chromosomes are European, 5% are African, and 1% are Amerind. Y-chromosome data are consistent with an origin of founders predominantly in southern Spain but also suggest that a fraction came from northern Iberia and that some possibly had a Sephardic origin. In stark contrast with the Y-chromosome, approximately 90% of the mtDNA gene pool of Antioquia is Amerind, with the frequency of the four Amerind founder lineages being closest to Native Americans currently living in the area. These results indicate a highly asymmetric pattern of mating in early Antioquia, involving mostly immigrant men and local native women. The discordance of our data with blood-group estimates of admixture suggests that the number of founder men was larger than that of women.

Historical and genetic evidences suggest that the recently founded population of Antioquia (Colombia) is potentially useful for the genetic mapping of complex traits. This population was established in the 16th-17th centuries through the admixture of Amerinds, Europeans, and Africans and grew in relative isolation until the late 19th century. To examine the origin of the founders of Antioquia, we typed 11 markers on the nonrecombining portion of the Y chromosome and four markers on mtDNA in a sample of individuals with confirmed Antioquian ancestry. The polymorphisms on the Y chromosome (five biallelic markers and six microsatellites) allow an approximation to the origin of founder men, and those on mtDNA identify the four major founder Native American lineages. These data indicate that approximately 94% of the Y chromosomes are European, 5% are African, and 1% are Amerind. Y-chromosome data are consistent with an origin of founders predominantly in southern Spain but also suggest that a fraction came from northern Iberia and that some possibly had a Sephardic origin. In stark contrast with the Y-chromosome, approximately 90% of the mtDNA gene pool of Antioquia is Amerind, with the frequency of the four Amerind founder lineages being closest to Native Americans currently living in the area. These results indicate a highly asymmetric pattern of mating in early Antioquia, involving mostly immigrant men and local native women. The discordance of our data with blood-group estimates of admixture suggests that the number of founder men was larger than that of women.

Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability.

Inflammation is endemic to obesity and type 2 diabetes (T2D) but it is unclear if it is a cause or a consequence. If the latter, then inflammation may increase the risk of obesity and diabetes complications. Large genome-wide association studies (GWAS) of inflammation and cardiometabolic traits can be used to investigate causal mechanisms. Summary statistics were assembled from GWAS of 49 cytokine (N=840-80,000) and 20 cardiometabolic traits (N=2,447-465,333). Shared genetic background was measured using LD score regression. Polygenic scores (PGS) were generated from GWAS data for 49 cytokines (representing inflammation) and 20 cardiometabolic traits and used in two-way Mendelian Randomisation (MR) analyses. Causal relationships were identified using summary statistics for all traits, and individual data (UK Biobank, N=465,333) to test the association of cytokine PGS with body mass index (BMI) and T2D. LD score regression analysis demonstrated that BMI and T2D shared a genetic background with acute phase cytokines. However, MR analyses showed that genetically-driven variation in cytokine levels were not associated with increased BMI or T2D risk. This argues against a causal role for inflammation (as represented by these cytokines) in the development of obesity and T2D. In contrast, genetically driven obesity was associated with increased inflammation: a PGS for increased BMI was associated with increased C-reactive protein (Beta [95% CI], 0.40 [0.34,0.46], p=1.3×10-36) and activated plasminogen inhibitor (Beta [95% CI], 0.39 [0.19, 0.59], p=7.8×10-5) levels. Genetically-driven variation in cytokine levels were causally linked with chronic kidney disease in subjects with T2D: fibroblast growth factor 2 (OR[95% CI], 0.58[0.46,0.72], p=1.8×10-6) and interleukin 13 (OR[95% CI], 1.28[1.15,1.43], p=7.0×10-6) We conclude that chronic inflammation is a consequence, rather than a cause, of T2D and obesity, and may contribute to some of their complications. Disclosure N. van Zuydam: None. M. Wielscher: None. M. McCarthy: Research Support; Self; Eli Lilly and Company, Takeda Pharmaceuticals U.S.A., Inc., Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S, Pfizer Inc.. Research Support; Self; Pfizer Inc., Sanofi, Boehringer Ingelheim GmbH, AstraZeneca, Merck Sharp & Dohme Corp.. M. Jarvelin: None.

AbstractResolving the molecular processes that mediate genetic risk remains a challenge as most disease-associated variants are non-coding and functional and bioinformatic characterization of these signals requires knowledge of the specific tissues and cell-types in which they operate. To address this challenge, we developed a framework for integrating tissue-specific gene expression and epigenomic maps (primarily from tissues involved in insulin secretion and action) to obtain tissue-of-action (TOA) scores for each association signal by systematically partitioning posterior probabilities from Bayesian fine-mapping. We applied this scheme to credible set variants for 380 association signals from a recent GWAS meta-analysis of type 2 diabetes (T2D) in Europeans. The resulting tissue profiles underscored a predominant role for pancreatic islets and, to a lesser extent, subcutaneous adipose and liver, that was largely attributable to enhancer elements and transcribed regions, particularly among signals with greater fine-mapping resolution. We incorporated resulting TOA scores into a rule-based classifier, and validated the tissue assignments through comparison with data from cis-eQTL enrichment, functional fine-mapping, RNA co-expression, and patterns of physiological association. In addition to implicating signals with a single tissue-of-action, we also found evidence for signals with shared effects in multiple tissues as well as distinct tissue profiles between independent signals within heterogeneous loci. Lastly, we demonstrated that TOA scores can be directly coupled with eQTL colocalization to further resolve effector transcripts at T2D signals. This framework guides mechanistic inference by directing functional validation studies to the most relevant tissues and can gain power as fine-mapping resolution and cell-specific annotations become richer. This method is generalizable to all complex traits with relevant annotation data and is made available as an R package.