Discovery Of 42 Genome-Wide Significant Loci Associated With Dyslexia

Reading and writing are crucial for many aspects of modern life but up to 1 in 10 children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet no convincing genetic markers have been found due to limited study power. Here, we present a genome-wide association study representing a 20-fold increase in sample size from prior work, with 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls. We identified 42 independent genome-wide significant loci: 17 are in genes linked to or pleiotropic with cognitive ability/educational attainment; 25 are novel and may be more specifically associated with dyslexia. Twenty-three loci (12 novel) were validated in independent cohorts of Chinese and European ancestry. We confirmed a similar genetic aetiology of dyslexia between sexes, and found genetic covariance with many traits, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Causal analyses revealed a directional effect of dyslexia on attention deficit hyperactivity disorder and bidirectional effects on socio-educational traits but these relationships require further investigation. Dyslexia polygenic scores explained up to 6% of variance in reading traits in independent cohorts, and might in future enable earlier identification and remediation of dyslexia.

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Genome-wide association study of delay discounting in 23,217 adult research participants of European ancestry

10.1101/146936 ◽

2017 ◽

Author(s):

Sandra Sanchez-Roige ◽

Pierre Fontanillas ◽

Sarah L. Elson ◽

Anita Pandit ◽

Ellen M. Schmidt ◽

...

Keyword(s):

Body Weight ◽

Association Study ◽

Delay Discounting ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

European Ancestry ◽

Research Participants ◽

Hyperactivity Disorder ◽

Genome Wide ◽

A Genome

ABSTRACTDelay discounting (DD), which is the tendency to discount the value of delayed versus current rewards, is elevated in a constellation of diseases and behavioral conditions. We performed a genome-wide association study of DD using 23,127 research participants of European ancestry. The most significantly associated SNP was rs6528024 (P = 2.40 × 10−8), which is located in an intron of the gene GPM6B. We also showed that 12% of the variance in DD was accounted for by genotype, and that the genetic signature of DD overlapped with attention-deficit/hyperactivity disorder, schizophrenia, major depression, smoking, personality, cognition, and body weight.

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Abstract P629: Genome-Wide Association Study of Individuals of Native Hawaiian Ancestry Reveals Unique Genetic Risk Factors for Stroke and Myocardial Infarction

Stroke ◽

10.1161/str.52.suppl_1.p629 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Stacy C Brown ◽

Cameron Both ◽

Julian N Acosta ◽

Natalia Szejko ◽

Victor Torres ◽

...

Keyword(s):

Myocardial Infarction ◽

Ischemic Stroke ◽

Association Study ◽

Genome Wide Association Study ◽

Native Hawaiian ◽

European Ancestry ◽

Intronic Region ◽

Genome Wide ◽

A Genome ◽

Risk Locus

Background: Several genetic susceptibility risk loci for ischemic stroke have been identified. However, the relative dearth of genetic data from populations of non-European ancestry has the potential to create disparities in access to genomics-based precision medicine strategies. Individuals of Native Hawaiian ancestry represent a particularly understudied group in stroke genomics research despite facing high rates of cerebrovascular disease. Hypothesis: Genetic variants associated with stroke differ between Native Hawaiians and previously studied groups of predominantly European ancestry. Methods: We conducted a genome-wide (GW) association study of stroke and myocardial infarction (MI) in an adult population of Native Hawaiian ancestry, using data from the Multiethnic Cohort study (MEC). Genetic information was ascertained via genome-wide array genotyping using the AB OpenArray and TaqMan platforms followed by imputation to 1000 Genomes reference panels. We pursued replication of variants that were GW significant (p<5x10 -8 ) or yielded suggestive associations (p<5x10 -7 ) in the prior stroke GW association study MEGASTROKE. Results: We identified 2,104 individuals (1,089 [51.8%] female) of Native Hawaiian ancestry, including 173 cases and 1,931 controls. We identified one novel susceptibility risk locus at a narrow intronic region located at chromosome q26.2 (top associated SNP 3:169096251, OR 2.48, 95%CI 1.81-3.41; p=1.93x10 -8 ), overlying the MECOM gene. We also identified 9 other suggestive risk loci at p<5x10 -7 . When replicating in MEGASTROKE, q26.2 did not have available counterpart variants to analyze, and 3 out of 9 suggestive signals were associated with ischemic stroke subtypes at p<0.05. Conclusions: We report the first GW association study of ischemic stroke and myocardial infarction in a Native Hawaiian population. We identified one susceptibility risk locus at q26.2, located in a narrow intronic region of MECOM, a gene that codes for a histone-lysine N-methyltransferase that has transcriptional regulation and oncoprotein functions. The lack of available replication data for this locus in the large MEGASTROKE collaboration emphasizes the importance of developing genomic resources across ancestral groups.

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Genome-wide polygenic score to identify a monogenic risk-equivalent for coronary disease

10.1101/218388 ◽

2017 ◽

Cited By ~ 9

Author(s):

Amit V. Khera ◽

Mark Chaffin ◽

Krishna G. Aragam ◽

Connor A. Emdin ◽

Derek Klarin ◽

...

Keyword(s):

Coronary Disease ◽

Fold Increase ◽

Predictive Capacity ◽

Cumulative Impact ◽

Polygenic Score ◽

Genome Wide ◽

A Genome ◽

Increased Risk ◽

Polygenic Scores ◽

Artery Disease

AbstractIdentification of individuals at increased genetic risk for a complex disorder such as coronary disease can facilitate treatments or enhanced screening strategies. A rare monogenic mutation associated with increased cholesterol is present in ~1:250 carriers and confers an up to 4-fold increase in coronary risk when compared with non-carriers. Although individual common polymorphisms have modest predictive capacity, their cumulative impact can be aggregated into a polygenic score. Here, we develop a new, genome-wide polygenic score that aggregates information from 6.6 million common polymorphisms and show that this score can similarly identify individuals with a 4-fold increased risk for coronary disease. In >400,000 participants from UK Biobank, the score conforms to a normal distribution and those in the top 2.5% of the distribution are at 4-fold increased risk compared to the remaining 97.5%. Similar patterns are observed with genome-wide polygenic scores for two additional diseases – breast cancer and severe obesity.One Sentence SummaryA genome-wide polygenic score identifies 2.5% of the population born with a 4-fold increased risk for coronary artery disease.

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Genome-wide association study identifies locus at chromosome 2q32.1 associated with syncope and collapse

Cardiovascular Research ◽

10.1093/cvr/cvz106 ◽

2019 ◽

Vol 116 (1) ◽

pp. 138-148 ◽

Cited By ~ 4

Author(s):

Katra Hadji-Turdeghal ◽

Laura Andreasen ◽

Christian M Hagen ◽

Gustav Ahlberg ◽

Jonas Ghouse ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

European Ancestry ◽

Psychiatric Research ◽

Carrier Status ◽

Genome Wide ◽

Common Genetic Variants ◽

A Genome ◽

Significant Locus

Abstract Aims Syncope is a common condition associated with frequent hospitalization or visits to the emergency department. Family aggregation and twin studies have shown that syncope has a heritable component. We investigated whether common genetic variants predispose to syncope and collapse. Methods and results We used genome-wide association data on syncope on 408 961 individuals with European ancestry from the UK Biobank study. In a replication study, we used the Integrative Psychiatric Research Consortium (iPSYCH) cohort (n = 86 189), to investigate the risk of incident syncope stratified by genotype carrier status. We report on a genome-wide significant locus located on chromosome 2q32.1 [odds ratio = 1.13, 95% confidence interval (CI) 1.10–1.17, P = 5.8 × 10−15], with lead single nucleotide polymorphism rs12465214 in proximity to the gene zinc finger protein 804a (ZNF804A). This association was also shown in the iPSYCH cohort, where homozygous carriers of the C allele conferred an increased hazard ratio (1.30, 95% CI 1.15–1.46, P = 1.68 × 10−5) of incident syncope. Quantitative polymerase chain reaction analysis showed ZNF804A to be expressed most abundantly in brain tissue. Conclusion We identified a genome-wide significant locus (rs12465214) associated with syncope and collapse. The association was replicated in an independent cohort. This is the first genome-wide association study to associate a locus with syncope and collapse.

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Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study

The Lancet Respiratory Medicine ◽

10.1016/s2213-2600(17)30387-9 ◽

2017 ◽

Vol 5 (11) ◽

pp. 869-880 ◽

Cited By ~ 94

Author(s):

Richard J Allen ◽

Joanne Porte ◽

Rebecca Braybrooke ◽

Carlos Flores ◽

Tasha E Fingerlin ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Association Study ◽

Genetic Variants ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide ◽

A Genome

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Genetic Effects on Longitudinal Cognitive Decline During the Early Stages of Alzheimer's Disease

10.21203/rs.3.rs-149163/v1 ◽

2021 ◽

Author(s):

Atul Kumar ◽

Maryam Shoai ◽

Sebastian Palmqvist ◽

Erik Stomrud ◽

John Hardy ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Genome Wide Association Study ◽

Early Stage ◽

Cognitive Change ◽

Preclinical Ad ◽

Genome Wide ◽

A Genome ◽

Polygenic Scores

Abstract Background Cognitive decline in early-stage Alzheimer’s disease (AD) may depend on genetic variability. Methods In the Swedish BioFINDER study, we used polygenic scores (PGS) (for AD, intelligence and educational attainment), and genetic variants (in a genome-wide association study [GWAS]) to predict longitudinal cognitive change (measured by MMSE) over a mean of 4.2 years. We included 555 β-amyloid (Aβ) negative cognitively unimpaired (CU) individuals, 206 Aβ-positive CU (preclinical AD), 110 Aβ-negative mild cognitive impairment (MCI) patients, and 146 Aβ-positive MCI patients (prodromal AD). Results Polygenic scores for AD (in Aβ-positive individuals) and intelligence (independent of Aβ-status) were associated with cognitive decline. Eight genes were associated with cognitive decline in GWAS (3 independent of Aβ-status). Conclusions AD risk genes may influence cognitive decline in early AD, while genes related to intelligence may modulate cognitive decline irrespective of disease. Therapies targeting the implicated biological pathways may modulate the clinical course of AD.

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Elucidating the genetic architecture underlying IGF1 levels and its impact on genomic instability and cancer risk

Wellcome Open Research ◽

10.12688/wellcomeopenres.16417.1 ◽

2021 ◽

Vol 6 ◽

pp. 20

Author(s):

Stasa Stankovic ◽

Felix R. Day ◽

Yajie Zhao ◽

Claudia Langenberg ◽

Nicholas J. Wareham ◽

...

Keyword(s):

Genomic Instability ◽

Genome Wide Association Study ◽

Genetic Regulation ◽

Epidemiological Studies ◽

European Ancestry ◽

Reverse Causality ◽

Lung Cancers ◽

Genome Wide ◽

A Genome ◽

The Uk

Background: Insulin-like growth factor-1 (IGF1) has been implicated in mitogenic and anti-apoptotic mechanisms that promote susceptibility to cancer development and growth. Previous epidemiological studies have described phenotypic associations between higher circulating levels of IGF1 in adults with higher risks for breast, prostate, ovarian, colorectal, melanoma and lung cancers. However, such evidence is prone to confounding and reverse causality. Furthermore, it is unclear whether IGF1 promotes only the survival and proliferation of cancerous cells, or also the malignant transformation of healthy cells. Methods: We perform a genome-wide association study in 428,525 white European ancestry individuals in the UK Biobank study (UKBB) and identify 831 independent genetic determinants of circulating IGF1 levels, double the number previously reported. Results: Collectively these signals explain ~7.5% of the variance in circulating IGF1 levels in EPIC-Norfolk, with individuals in the highest 10% of genetic risk exhibiting ~1 SD higher levels than those in the lowest 10%. Using a Mendelian randomization approach, we demonstrate that genetically higher circulating IGF1 levels are associated with greater likelihood of mosaic loss of chromosome Y in leukocytes in men in UKBB (OR per +1 SD = 1.038 (95% CI: 1.010-1.067), P=0.008) and 23andMe, Inc. (P=6.8×10-05), a biomarker of genomic instability involved in early tumorigenesis. Genetically higher IGF1 is also associated with higher risks for colorectal (OR = 1.126 (1.048-1.210), P=1.3×10-03) and breast cancer (OR= 1.075 (1.048-1.103), P=3.9×10-08), with similar effects on estrogen positive (ER+) (OR = 1.069 (1.037-1.102), P=2.3×10-05) and estrogen negative (ER-) (OR = 1.074 (1.025-1.125), P=3.9×10-08) subtypes. Conclusions: These findings give an insight into the genetic regulation of circulating IGF1 levels and support a causal role for IGF1 in early tumorigenesis and risks for breast and colorectal cancers.

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Abstract 051: Genome-wide Association Study Identifies 12 Loci for Habitual Consumption of Bitter and Sweet Beverages

Circulation ◽

10.1161/circ.137.suppl_1.051 ◽

2018 ◽

Vol 137 (suppl_1) ◽

Author(s):

Victor W Zhong ◽

Sandra Sanchez-Roige ◽

Peter Kraft ◽

Rob M Van Dam ◽

Daniel I Chasman ◽

...

Keyword(s):

Chronic Disease ◽

Association Study ◽

Genome Wide Association Study ◽

Genetic Model ◽

Taste Perception ◽

Genome Wide Association ◽

European Ancestry ◽

Multiple Snps ◽

Genome Wide ◽

A Genome

Introduction: Widely consumed beverages (e.g., soft drinks, coffee, tea) are critical sources of energy, added sugar and phytochemicals and are associated with obesity and chronic disease. Taste perception and preferences are highly heritable and strong determinants of food and beverage choice. We aimed to identify novel loci underlying habitual bitter and sweet beverage intake. Methods: We performed a genome-wide association study (GWAS) of self-reported bitter and sweet beverage intake in participants of European ancestry in the UK Biobank. Diet was assessed via multiple 24-h diet recalls (n=84703, subset) or questionnaire (n=335909, all). Bitter beverage intake was the sum of coffee, tea and grapefruit juice. Sweet beverage intake was the sum of artificially and sugar sweetened beverages and other fruit juice. Multivariable linear regression under an additive genetic model was applied. GW-significant (P < 5х10 -8 ) SNPs were followed-up for replication in independent studies of European ancestry. Results: Multiple SNPs spanning 11 loci were associated with bitter beverage intake (P <5х10 -8 , Table 1), and at least 5 of them reflected the caffeine content of coffee and tea. Multiple SNPs in the obesity candidate gene FTO were associated with sweet beverage intake (P <5х10 -8 ). The effect size per allele ranged from 0.02 to 0.2 cup per day. Loci in/near AHR, CYP1A2, and FTO were associated with both bitter and sweet beverage intake but in opposite directions. Replication efforts are ongoing. So far, associations at all loci, except 1q25.2 and 2q36.2, were replicated (P range: 0.04 to 1.8x10 -8 ) in independent studies (n=17322) which provided 80% power for replicating 8 of these 12 loci at P=0.05. Conclusions: Loci linked to caffeine metabolism and obesity predisposition rather than taste are major determinants of beverage intake. These and other identified loci have been linked to chronic disease and risk factors, suggesting causal or pleiotropic effects. Our findings have potential public health and methodological implications.

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