An Expanded View of Complex Traits: From Polygenic to Omnigenic

A main challenge in genome-wide association studies (GWAS) is to pinpoint possible causal variants. Results from GWAS typically do not directly translate into causal variants because the majority of hits are in non-coding or intergenic regions, and the presence of linkage disequilibrium leads to effects being statistically spread out across multiple variants. Post-GWAS annotation facilitates the selection of most likely causal variant(s). Multiple resources are available for post-GWAS annotation, yet these can be time consuming and do not provide integrated visual aids for data interpretation. We, therefore, develop FUMA: an integrative web-based platform using information from multiple biological resources to facilitate functional annotation of GWAS results, gene prioritization and interactive visualization. FUMA accommodates positional, expression quantitative trait loci (eQTL) and chromatin interaction mappings, and provides gene-based, pathway and tissue enrichment results. FUMA results directly aid in generating hypotheses that are testable in functional experiments aimed at proving causal relations.

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Functional mapping and annotation of genetic associations with FUMA

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

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Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression

Metabolic syndrome, variously known also as syndrome X, insulin resistance, etc., is defined by WHO as a pathologic condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Though there is some variation in the definition by other health care organization, the differences are minor. With the successful conquest of communicable infectious diseases in most of the world, this new non-communicable disease (NCD) has become the major health hazard of modern world. Though it started in the Western world, with the spread of the Western lifestyle across the globe, it has become now a truly global problem. The prevalence of the metabolic syndrome is often more in the urban population of some developing countries than in its Western counterparts. The two basic forces spreading this malady are the increase in consumption of high calorie-low fiber fast food and the decrease in physical activity due to mechanized transportations and sedentary form of leisure time activities. The syndrome feeds into the spread of the diseases like type 2 diabetes, coronary diseases, stroke, and other disabilities. The total cost of the malady including the cost of health care and loss of potential economic activity is in trillions. The present trend is not sustainable unless a magic cure is found (unlikely) or concerted global/governmental/societal efforts are made to change the lifestyle that is promoting it. There are certainly some elements in the causation of the metabolic syndrome that cannot be changed but many are amenable for corrections and curtailments. For example, better urban planning to encourage active lifestyle, subsidizing consumption of whole grains and possible taxing high calorie snacks, restricting media advertisement of unhealthy food, etc. Revitalizing old fashion healthier lifestyle, promoting old-fashioned foods using healthy herbs rather than oil and sugar, and educating people about choosing healthy/wholesome food over junks are among the steps that can be considered.

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The Global Epidemic of the Metabolic Syndrome.

Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with human complex traits. However, the genes or functional DNA elements through which these variants exert their effects on the traits are often unknown. We propose a method (called SMR) that integrates summary-level data from GWAS with data from expression quantitative trait locus (eQTL) studies to identify genes whose expression levels are associated with a complex trait because of pleiotropy. We apply the method to five human complex traits using GWAS data on up to 339,224 individuals and eQTL data on 5,311 individuals, and we prioritize 126 genes (for example, TRAF1 and ANKRD55 for rheumatoid arthritis and SNX19 and NMRAL1 for schizophrenia), of which 25 genes are new candidates; 77 genes are not the nearest annotated gene to the top associated GWAS SNP. These genes provide important leads to design future functional studies to understand the mechanism whereby DNA variation leads to complex trait variation.

Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets

Obesity is heritable and predisposes to many diseases To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals This analysis identifies 97 BMI-associated loci (P 20% of BMI variation Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis

https://scholarspace.manoa.hawaii.edu/bitstream/10125/40202/1/nihms-668049%281%29.pdf

Magic Investigators

Papers

Genetic studies of body mass index yield new insights for obesity biology