Discovery of 42 genome-wide significant loci associated with dyslexia

Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls and identified 42 independent genome-wide significant loci: 15 in genes linked to cognitive ability/educational attainment, and 27 new and potentially more specific to dyslexia. We validated 23 loci (13 new) in independent cohorts of Chinese and European ancestry. Genetic etiology of dyslexia was similar between sexes, and genetic covariance with many traits was found, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Dyslexia polygenic scores explained up to 6% of variance in reading traits, and might in future contribute to earlier identification and remediation of dyslexia. [Abstract copyright: © 2022. The Author(s).

A genome-wide cross-phenotype meta-analysis of the association of blood pressure with migraine

Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine (Ncases/Ncontrols = 59,674/316,078) and BP (N = 757,601), we find positive genetic correlations of migraine with diastolic BP (DBP, rg = 0.11, P = 3.56 × 10-06) and systolic BP (SBP, rg = 0.06, P = 0.01), but not pulse pressure (PP, rg = -0.01, P = 0.75). Cross-trait meta-analysis reveals 14 shared loci (P ≤ 5 × 10-08), nine of which replicate (P < 0.05) in the UK Biobank. Five shared loci (ITGB5, SMG6, ADRA2B, ANKDD1B, and KIAA0040) are reinforced in gene-level analysis and highlight potential mechanisms involving vascular development, endothelial function and calcium homeostasis. Mendelian randomization reveals stronger instrumental estimates of DBP (OR [95% CI] = 1.20 [1.15-1.25]/10 mmHg; P = 5.57 × 10-25) on migraine than SBP (1.05 [1.03-1.07]/10 mmHg; P = 2.60 × 10-07) and a corresponding opposite effect for PP (0.92 [0.88-0.95]/10 mmHg; P = 3.65 × 10-07). These findings support a critical role of DBP in migraine susceptibility and shared biology underlying BP and migraine

Evaluating Lipid-Lowering Drug Targets for Parkinson's Disease Prevention with Mendelian Randomization

Long-term exposure to lipid-lowering drugs might affect Parkinson's disease (PD) risk. We conducted Mendelian randomization analyses where genetic variants indexed expected effects of modulating lipid-lowering drug targets on PD. Statin exposure was not predicted to increase PD risk, although results were not precise enough to support benefits for prevention clearly (odds ratio [OR] = 0.83; 95% confidence interval [CI] = 0.65, 1.07). Other target results were null, except for variants indicating Apolipoprotein-A5 or Apolipoprotein-C3 inhibition might confer protection. These findings suggest peripheral lipid variation may not have a prominent role in PD etiology, but some related drug targets could influence PD via alternate pathways. ANN NEUROL 2020;88:1043–104

The Parkinson's phenome-traits associated with Parkinson's disease in a broadly phenotyped cohort

In order to systematically describe the Parkinson's disease phenome, we performed a series of 832 cross-sectional case-control analyses in a large database. Responses to 832 online survey-based phenotypes including diseases, medications, and environmental exposures were analyzed in 23andMe research participants. For each phenotype, survey respondents were used to construct a cohort of Parkinson's disease cases and age-matched and sex-matched controls, and an association test was performed using logistic regression. Cohorts included a median of 3899 Parkinson's disease cases and 49,808 controls, all of European ancestry. Highly correlated phenotypes were removed and the novelty of each significant association was systematically assessed (assigned to one of four categories: known, likely, unclear, or novel). Parkinson's disease diagnosis was associated with 122 phenotypes. We replicated 27 known associations and found 23 associations with a strong a priori link to a known association. We discovered 42 associations that have not previously been reported. Migraine, obsessive-compulsive disorder, and seasonal allergies were associated with Parkinson's disease and tend to occur decades before the typical age of diagnosis for Parkinson's disease. The phenotypes that currently comprise the Parkinson's disease phenome have mostly been explored in relatively small purpose-built studies. Using a single large dataset, we have successfully reproduced many of these established associations and have extended the Parkinson's disease phenome by discovering novel associations. Our work paves the way for studies of these associated phenotypes that explore shared molecular mechanisms with Parkinson's disease, infer causal relationships, and improve our ability to identify individuals at high-risk of Parkinson's disease

Genetic analyses identify widespread sex-differential participation bias

Genetic analyses identify widespread sex-differential participation bias in population-based studies and show how this bias can lead to incorrect inferences. These findings highlight new challenges for association studies as sample sizes continue to grow. Genetic association results are often interpreted with the assumption that study participation does not affect downstream analyses. Understanding the genetic basis of participation bias is challenging since it requires the genotypes of unseen individuals. Here we demonstrate that it is possible to estimate comparative biases by performing a genome-wide association study contrasting one subgroup versus another. For example, we showed that sex exhibits artifactual autosomal heritability in the presence of sex-differential participation bias. By performing a genome-wide association study of sex in approximately 3.3 million males and females, we identified over 158 autosomal loci spuriously associated with sex and highlighted complex traits underpinning differences in study participation between the sexes. For example, the body mass index-increasing allele at FTO was observed at higher frequency in males compared to females (odds ratio = 1.02, P = 4.4 x 10(-)(36)). Finally, we demonstrated how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow.Peer reviewe

Genetic analysis of endometriosis and depression identifies shared loci and implicates causal links with gastric mucosa abnormality

Evidence from observational studies indicates that endometriosis and depression often co-occur. However, conflicting evidence exists, and the etiology as well as biological mechanisms underlying their comorbidity remain unknown. Utilizing genome-wide association study (GWAS) data, we comprehensively assessed the relationship between endometriosis and depression. Single nucleotide polymorphism effect concordance analysis (SECA) found a significant genetic overlap between endometriosis and depression (P  = 9.99 × 10 ). Linkage disequilibrium score regression (LDSC) analysis estimated a positive and highly significant genetic correlation between the two traits (r  = 0.27, P = 8.85 × 10 ). A meta-analysis of endometriosis and depression GWAS (sample size = 709,111), identified 20 independent genome-wide significant loci (P < 5 × 10 ), of which eight are novel. Mendelian randomization analysis (MR) suggests a causal effect of depression on endometriosis. Combining gene-based association results across endometriosis and depression GWAS, we identified 22 genes with a genome-wide significant Fisher's combined P value (FCP  < 2.75 × 10 ). Genes with a nominal gene-based association (P  < 0.05) were significantly enriched across endometriosis and depression (P  = 2.90 × 10 ). Also, genes overlapping the two traits at P  < 0.1 (P  = 1.31 × 10 ) were significantly enriched for the biological pathways 'cell-cell adhesion', 'inositol phosphate metabolism', 'Hippo-Merlin signaling dysregulation' and 'gastric mucosa abnormality'. These results reveal a shared genetic etiology for endometriosis and depression. Indeed, additional analyses found evidence of a causal association between each of endometriosis and depression and at least one abnormal condition of gastric mucosa. Our study confirms the comorbidity of endometriosis and depression, implicates links with gastric mucosa abnormalities in their causal pathways and reveals potential therapeutic targets for further investigation

Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan

The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes

A genome-wide cross-phenotype meta-analysis of the association of blood pressure with migraine.

Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine (Ncases/Ncontrols = 59,674/316,078) and BP (N = 757,601), we find positive genetic correlations of migraine with diastolic BP (DBP, rg = 0.11, P = 3.56 × 10-06) and systolic BP (SBP, rg = 0.06, P = 0.01), but not pulse pressure (PP, rg = -0.01, P = 0.75). Cross-trait meta-analysis reveals 14 shared loci (P ≤ 5 × 10-08), nine of which replicate (P < 0.05) in the UK Biobank. Five shared loci (ITGB5, SMG6, ADRA2B, ANKDD1B, and KIAA0040) are reinforced in gene-level analysis and highlight potential mechanisms involving vascular development, endothelial function and calcium homeostasis. Mendelian randomization reveals stronger instrumental estimates of DBP (OR [95% CI] = 1.20 [1.15-1.25]/10 mmHg; P = 5.57 × 10-25) on migraine than SBP (1.05 [1.03-1.07]/10 mmHg; P = 2.60 × 10-07) and a corresponding opposite effect for PP (0.92 [0.88-0.95]/10 mmHg; P = 3.65 × 10-07). These findings support a critical role of DBP in migraine susceptibility and shared biology underlying BP and migraine

Genome-wide association study of problematic opioid prescription use in 132,113 23andMe research participants of European ancestry

The growing prevalence of opioid use disorder (OUD) constitutes an urgent health crisis. Ample evidence indicates that risk for OUD is heritable. As a surrogate (or proxy) for OUD, we explored the genetic basis of using prescription opioids \u27not as prescribed\u27. We hypothesized that misuse of opiates might be a heritable risk factor for OUD. To test this hypothesis, we performed a genome-wide association study (GWAS) of problematic opioid use (POU) in 23andMe research participants of European ancestry (N = 132,113; 21% cases). We identified two genome-wide significant loci (rs3791033, an intronic variant of KDM4A; rs640561, an intergenic variant near LRRIQ3). POU showed positive genetic correlations with the two largest available GWAS of OUD and opioid dependence (

Influence of autozygosity on common disease risk across the phenotypic spectrum.

Autozygosity is associated with rare Mendelian disorders and clinically relevant quantitative traits. We investigated associations between the fraction of the genome in runs of homozygosity (FROH) and common diseases in Genes & Health (n = 23,978 British South Asians), UK Biobank (n = 397,184), and 23andMe. We show that restricting analysis to offspring of first cousins is an effective way of reducing confounding due to social/environmental correlates of FROH. Within this group in G&H+UK Biobank, we found experiment-wide significant associations between FROH and twelve common diseases. We replicated associations with type 2 diabetes (T2D) and post-traumatic stress disorder via within-sibling analysis in 23andMe (median n = 480,282). We estimated that autozygosity due to consanguinity accounts for 5%-18% of T2D cases among British Pakistanis. Our work highlights the possibility of widespread non-additive genetic effects on common diseases and has important implications for global populations with high rates of consanguinity