Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese

OBJECTIVES This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk. BACKGROUND AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored. METHODS We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases). RESULTS We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements. CONCLUSIONS The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

A Genome-Wide Association Study Reveals Loci Influencing Height and Other Conformation Traits in Horses

The molecular analysis of genes influencing human height has been notoriously difficult. Genome-wide association studies (GWAS) for height in humans based on tens of thousands to hundreds of thousands of samples so far revealed ∼200 loci for human height explaining only 20% of the heritability. In domestic animals isolated populations with a greatly reduced genetic heterogeneity facilitate a more efficient analysis of complex traits. We performed a genome-wide association study on 1,077 Franches-Montagnes (FM) horses using ∼40,000 SNPs. Our study revealed two QTL for height at withers on chromosomes 3 and 9. The association signal on chromosome 3 is close to the LCORL/NCAPG genes. The association signal on chromosome 9 is close to the ZFAT gene. Both loci have already been shown to influence height in humans. Interestingly, there are very large intergenic regions at the association signals. The two detected QTL together explain ∼18.2% of the heritable variation of height in horses. However, another large fraction of the variance for height in horses results from ECA 1 (11.0%), although the association analysis did not reveal significantly associated SNPs on this chromosome. The QTL region on ECA 3 associated with height at withers was also significantly associated with wither height, conformation of legs, ventral border of mandible, correctness of gaits, and expression of the head. The region on ECA 9 associated with height at withers was also associated with wither height, length of croup and length of back. In addition to these two QTL regions on ECA 3 and ECA 9 we detected another QTL on ECA 6 for correctness of gaits. Our study highlights the value of domestic animal populations for the genetic analysis of complex traits.

Comparative analysis of Tritrichomonas foetus (Riedmüller, 1928) cat genotype, T. foetus (Riedmüller, 1928) cattle genotype and Tritrichomonas suis (Davaine, 1875) at 10 DNA loci.

The parasitic protists in the genus Tritrichomonas cause significant disease in domestic cattle and cats. To assess the genetic diversity of feline and bovine isolates of Tritrichomonas foetus (Riedmüller, 1928) Wenrich and Emmerson, 1933, we used 10 different genetic regions, namely the protein coding genes of cysteine proteases 1, 2 and 4-9 (CP1, 2, 4-9) involved in the pathogenesis of the disease caused by the parasite. The cytosolic malate dehydrogenase 1 (MDH1) and internal transcribed spacer region 2 of the rDNA unit (ITS2) were included as additional markers. The gene sequences were compared with those of Tritrichomonas suis (Davaine, 1875) Morgan and Hawkins, 1948 and Tritrichomonas mobilensisCulberson et al., 1986. The study revealed 100% identity for all 10 genes among all feline isolates (=T. foetus cat genotype), 100% identity among all bovine isolates (=T. foetus cattle genotype) and a genetic distinctness of 1% between the cat and cattle genotypes of T. foetus. The cattle genotype of T. foetus was 100% identical to T. suis at nine loci (CP1, 2, 4-8, ITS2, MDH1). At CP9, three out of four T. suis isolates were identical to the T. foetus cattle genotype, while the T. suis isolate SUI-H3B sequence contained a single unique nucleotide substitution. Tritrichomonas mobilensis was 0.4% and 0.7% distinct from the cat and cattle genotypes of T. foetus, respectively. The genetic differences resulted in amino acid changes in the CP genes, most pronouncedly in CP2, potentially providing a platform for elucidation of genotype-specific host-pathogen interactions of T. foetus. On the basis of this data we judge T. suis and T. foetus to be subjective synonyms. For the first time, on objective nomenclatural grounds, the authority of T. suis is given to Davaine, 1875, rather than the commonly cited Gruby and Delafond, 1843. To maintain prevailing usage of T. foetus, we are suppressing the senior synomym T. suisDavaine, 1875 according to Article 23.9, because it has never been used as a valid name after 1899 and T. foetus is widely discussed as the cause of bovine trichomonosis. Thus bovine, feline and porcine isolates should all be given the name T. foetus. This promotes the stability of T. foetus for the veterinary and economically significant venereal parasite causing bovine trichomonosis.

Living in Heterogeneous Woodlands – Are Habitat Continuity or Quality Drivers of Genetic Variability in a Flightless Ground Beetle?

Although genetic diversity is one of the key components of biodiversity, its drivers are still not fully understood. While it is known that genetic diversity is affected both by environmental parameters as well as habitat history, these factors are not often tested together. Therefore, we analyzed 14 microsatellite loci in Abax parallelepipedus, a flightless, forest dwelling ground beetle, from 88 plots in two study regions in Germany. We modeled the effects of historical and environmental variables on allelic richness, and found for one of the regions, the Schorfheide-Chorin, a significant effect of the depth of the litter layer, which is a main component of habitat quality, and of the sampling effort, which serves as an inverse proxy for local population size. For the other region, the Schwäbische Alb, none of the potential drivers showed a significant effect on allelic richness. We conclude that the genetic diversity in our study species is being driven by current local population sizes via environmental variables and not by historical processes in the studied regions. This is also supported by lack of genetic differentiation between local populations sampled from ancient and from recent woodlands. We suggest that the potential effects of former fragmentation and recolonization processes have been mitigated by the large and stable local populations of Abax parallelepipedus in combination with the proximity of the ancient and recent woodlands in the studied landscapes.

Expansion load: recessive mutations and the role of standing genetic variation

Expanding populations incur a mutation burden – the so-called expansion load. Previous studies of expansion load have focused on codominant mutations. An important consequence of this assumption is that expansion load stems exclusively from the accumulation of new mutations occurring in individuals living at the wave front. Using individual-based simulations, we study here the dynamics of standing genetic variation at the front of expansions, and its consequences on mean fitness if mutations are recessive. We find that deleterious genetic diversity is quickly lost at the front of the expansion, but the loss of deleterious mutations at some loci is compensated by an increase of their frequencies at other loci. The frequency of deleterious homozygotes therefore increases along the expansion axis, whereas the average number of deleterious mutations per individual remains nearly constant across the species range. This reveals two important differences to codominant models: (i) mean fitness at the front of the expansion drops much faster if mutations are recessive, and (ii) mutation load can increase during the expansion even if the total number of deleterious mutations per individual remains constant. We use our model to make predictions about the shape of the site frequency spectrum at the front of range expansion, and about correlations between heterozygosity and fitness in different parts of the species range. Importantly, these predictions provide opportunities to empirically validate our theoretical results. We discuss our findings in the light of recent results on the distribution of deleterious genetic variation across human populations and link them to empirical results on the correlation of heterozygosity and fitness found in many natural range expansions.

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.