You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.

Title: Whole Exome Sequencing in Atrial Fibrillation}
Article:
Abstract:
Atrial fibrillation( AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1, 734 individuals with and 9, 423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes( N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8, 656( 78%) were of European ancestry. None of the 99, 404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common( allele frequency = 86%) missense variant in SYNPO2L( rs3812629, p. Pro707Leu,[odds ratio 1. 27, 95% confidence interval 1. 13–1. 43, P = 6. 6x10-5]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects.
Introduction:
Atrial fibrillation( AF) is a common[1, 2] arrhythmia associated with substantial morbidity[3–7]. Current treatments for AF have limited efficacy and can cause significant adverse effects[8, 9]. AF is heritable and approximately one in four individuals with AF has a first-degree relative with the condition[10]. In recent years a large number of genes have been implicated in AF risk using both genome-wide association studies and candidate gene screening approaches. Large-scale genome-wide association studies have identified multiple AF susceptibility loci[11–15], and the top variants at discovered loci have largely been localized to noncoding regions of the genome. In contrast, there have been over 35 genes implicated in AF in candidate gene studies[16]. These studies have had a number of limitations including small sample sizes, consideration of only one or a small number of genes, and the lack of suitable control populations. To date, large-scale studies to determine whether these genes are truly related to AF have not been performed. Since the discovery of genes causally related to AF may enable a better understanding of AF pathogenesis and potentially inform the development of therapies for AF, there is a critical need to systematically identify the genetic basis of AF. We therefore sought to assess the relations between coding variation and AF in a large sample of individuals who underwent whole exome sequencing. We further sought to determine whether coding variation in genes implicated in AF was enriched among AF cases.
Discussion:
In our sample of 1, 734 individuals with and 9, 423 without AF who underwent whole exome sequencing, we did not observe any rare coding variation significantly associated with AF. Our observations suggest that coding variation with large effect sizes is unlikely to be the predominant mechanism underlying common forms of AF. Our results extend prior literature focusing on coding variation underlying AF. Numerous reports propose coding variation as a mechanism underlying AF( S1 Table). However, much of the prior literature was generated via candidate gene association studies. Such discoveries have not been routinely replicated, and the studies were of small size, potentially favoring spurious results. Indeed, we previously observed that most findings from prior AF candidate gene association studies were not replicated when tested in additional study samples[17]. In the context of prior literature and our sample size, our study has two major implications for understanding AF pathogenesis. First, the lack of observed association between coding variation and AF implies that large effect coding variation is not likely to be common in typical forms of AF. In contrast, both noncoding variation, and coding variation with smaller effect sizes, may contribute to AF pathogenesis. Genome-wide association studies have identified highly associated common genetic variants near ion channels, cardiac and pulmonary transcription factors, and other genes in individuals with AF[11–15], underscoring the polygenic nature of AF. Nevertheless, the causal variants and genes underlying the arrhythmia remain unknown. Future whole-genome sequencing efforts may help to clarify the genetic contributions to AF. Second, our findings suggest that efforts to identify potential therapeutic targets for AF through exome sequencing analyses will require much larger sample sizes or populations enriched for large genetic effects. Such populations might include those with early onset AF or consanguineous populations with the propensity to homozygous loss of function alleles in genes. Nevertheless, the additional cost required to sequence such large populations must be balanced against the potentially more cost-efficient approach of performing GWAS genotyping, imputation, and subsequent functional characterization for genetic discovery. The lack of observation of any prominent coding variation underlying AF is consistent with other whole exome sequencing efforts of complex diseases such as coronary disease and diabetes[20], which generally have not identified coding variation as the major mechanisms underlying these conditions. Our study should be interpreted in the context of the study design. Our study was predominantly comprised of individuals of European ancestry, and therefore the findings may not be generalizable to other ancestral groups. The individuals with AF may have had multiple etiologies for the condition, and may not have been enriched for genetic forms of the arrhythmia. We cannot exclude that AF may have been misclassified, especially since AF may be paroxysmal and asymptomatic at times. Such misclassification is expected to bias the results toward the null. Furthermore, our study had limited power to assess the role of many coding variants, particularly because classifying missense variants as pathogenic or not remains challenging despite the routine use of bioinformatic algorithms. An earlier report of whole exome sequencing in 6 families with AF has summarized some of the bioinformatics challenges of utilizing whole exome sequencing data[21]. The size of our study sample limited our ability to detect potentially functional rare variants. Additionally, we utilized a Bonferroni significance threshold, which may be overly conservative for genetic discovery. In conclusion, we observed that coding variation is not a major contributor to AF in a sample of individuals predominantly of European ancestry. Efforts to identify coding variation underlying AF will require much larger study samples. Future analyses that integrate coding and noncoding variation, such as whole genome sequencing, are warranted.
Atrial fibrillation is a common and morbid cardiac arrhythmia . Atrial fibrillation is heritable , and numerous genome-wide susceptibility loci have been identified , predominantly in non-coding regions . Over 35 genes also have been implicated in atrial fibrillation pathogenesis mostly through prior smaller scale candidate gene association studies , which generally did not have robust replication to support the associations . Therefore , the role of coding variation in the biology of atrial fibrillation is unclear . We examined whole exome sequencing data from 1 , 734 individuals with and 9 , 423 without atrial fibrillation , and did not observe any significant associations between coding variation and the arrhythmia . Furthermore , we did not observe any enrichment for association in previously implicated atrial fibrillation genes . In aggregate , our findings suggest that large effect coding variation is unlikely to be a predominant mechanism of common forms of atrial fibrillation encountered in the community .