Leveraging Polygenic Functional Enrichment to Improve GWAS Power

Kichaev, Gleb; Bhatia, Gaurav; Loh, Po Ru; Gazal, Steven; Burch, Kathryn S.; Freund, Malika K.; Schoech, Armin; Paşaniuc, Bogdan; Price, Alkes L.

doi:10.1016/j.ajhg.2018.11.008

Cited by 830 publications

(798 citation statements)

References 59 publications

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“…The role of IFITM proteins in human allergic asthma has to our knowledge not been investigated, but genomewide association studies have linked IFITM2 and/or IFITM3 variants to potentially relevant traits, such as the proportion or count of basophils and eosinophils in blood, and lung function. 70,71 Given the link between IFITM and Hh signalling and the fact that Hh signalling has also been shown to promote Th2 differentiation and exacerbate allergic asthma, it will be important to investigate the interactions between IFITM proteins and the Hh pathway in allergic asthma. 11,[72][73][74][75][76][77] The IFITM proteins are associated with other atopic and inflammatory diseases.…”

Section: The Ifitm Family In Allergic and Inflammatory Diseasementioning

confidence: 99%

The IFITM protein family in adaptive immunity

2019

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Summary Interferon‐inducible transmembrane (IFITM) proteins are a family of small homologous proteins, localized in the plasma and endolysosomal membranes, which confer cellular resistance to many viruses. In addition, several distinct functions have been associated with different IFITM family members, including germ cell specification (IFITM1–IFITM3), osteoblast function and bone mineralization (IFITM5) and immune functions (IFITM1–3, IFITM6). IFITM1–3 are expressed by T cells and recent experiments have shown that the IFITM proteins are directly involved in adaptive immunity and that they regulate CD4+ T helper cell differentiation in a T‐cell‐intrinsic manner. Here we review the role of the IFITM proteins in T‐cell differentiation and function.

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Section: The Ifitm Family In Allergic and Inflammatory Diseasementioning

confidence: 99%

The IFITM protein family in adaptive immunity

2019

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“…From this GWAS, we report seven novel loci, defined as having no previously-reported associations in cognitive GWASs (Table S18). However, some of these loci have been associated with schizophrenia, (33) antisaccade response, (34) developmental language disorder (linguistic errors), (35) hand grip strength, (36) and bone mineral density (37) (Table S25).…”

Section: Resultsmentioning

confidence: 99%

Genetic “General Intelligence,” Objectively Determined and Measured

Fuente

Davies

Grotzinger

et al. 2019

Preprint

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It has been known for 115 years that, in humans, diverse cognitive traits are positively intercorrelated; this forms the basis for the general factor of intelligence (g). We directly test for a genetic basis for g using data from seven different cognitive tests (N = 11,263 to N = 331,679) and genome-wide autosomal single nucleotide polymorphisms. A genetic g factor accounts for 58.4% (SE = 4.8%) of the genetic variance in the cognitive traits, with trait-specific genetic factors accounting for the remaining 41.6%. We distill genetic loci broadly relevant for many cognitive traits (g) from loci associated with only individual cognitive traits. These results elucidate the etiological basis for a long-known yet poorly-understood phenomenon, revealing a fundamental dimension of genetic sharing across diverse cognitive traits.Genetic General Intelligence (g) Genetic "General Intelligence," Objectively Determined and Measured § § The title adds the word Genetic to the start of Spearman's 1904 title that discovered phenotypic general intelligence, which he abbreviated as g Scores on psychometric tests of cognitive abilities (intelligence) robustly predict educational performance, socio-economic attainments, everyday functioning, health, and longevity (1-3). In 1904, Charles Spearman identified a positive manifold of intercorrelations among school test results and estimates of intelligence, leading him to propose that they arise from a single general dimension of variation, which he termed general intelligence (and which he denoted as g) (4). He theorized that most of the remaining variance in each cognitive test was accounted for by a factor specific to that test, which he called s. Thus, some variance in each cognitive test is shared with all other cognitive tests (g), and some is specific to that test (its s). Hundreds of studies have since replicated the finding that, when several or many diverse cognitive tests are administered to a sizeable sample of people, a g factor is found that accounts for about 40% of the total test variance (5,6). Considerable efforts over the past century have been placed on identifying the biological bases of g, spanning levels of analysis from molecular, to neuroanatomical, to cognitive (7-11).Psychometrically, a hierarchical structure of cognitive abilities is commonly agreed, with cognitive tests' variance accounted for by three different strata of variation (Fig. S1), representing each test's specific variance (s), broad domains of cognitive function (e.g. reasoning, processing speed, memory), and g (5). Most twin studies that examine the heritability of human intelligence differences use test scores that mix g and s; relatively few have applied the twin method to the hierarchy of cognitive test score variance (12). The twin-based studies that have separated g variance from s variance indicate a strong heritable basis for g, suggesting that cognitive traits are positively correlated substantially because of strongly overlapping genetic architecture (13-17). These findings are consist...

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“…For instance, rs9818780 was associated with melanoma and has been implicated in sunburn risk. 37 This intergenic variant is an eQTL for LINC00886 and METTL15P1 in skin tissue. The former gene has previously been linked to breast cancer, 38 and both genes have been implicated in ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

Pan-Cancer Study Detects Novel Genetic Risk Variants and Shared Genetic Basis in Two Large Cohorts

Rashkin¹,

Graff

Kachuri³

et al. 2019

Preprint

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Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. However, no studies have investigated pan-cancer pleiotropy within single, well-defined populations unselected for phenotype. We undertook novel genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (413,870 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detected 21 novel genome-wide significant risk variants. In addition, numerous cancer sites exhibited clear heritability.Investigations of pleiotropy identified 12 cancer pairs exhibiting either positive or negative genetic correlations and 43 pleiotropic loci. We identified 158 pleiotropic variants, many of which were enriched for regulatory elements and influenced cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.

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Leveraging Polygenic Functional Enrichment to Improve GWAS Power

Cited by 830 publications

References 59 publications

The IFITM protein family in adaptive immunity

The IFITM protein family in adaptive immunity

Genetic “General Intelligence,” Objectively Determined and Measured

Pan-Cancer Study Detects Novel Genetic Risk Variants and Shared Genetic Basis in Two Large Cohorts

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