The genetic architecture of Parkinson disease in Spain: characterizing population-specific risk, differential haplotype structures, and providing etiologic insight

ABSTRACTBackgroundThe Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases.ObjectivesTo perform the largest Parkinson disease (PD) genome-wide association study (GWAS) restricted to a single country.MethodsWe performed a GWAS for both risk of PD and age-at-onset (AAO) in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations and burden analyses.ResultsWe identified a novel population-specific GWAS signal atPARK2associated with AAO. We replicated four genome-wide independent signals associated with PD risk, includingSNCA, LRRK2, KANSL1/MAPTandHLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence via two-sample Mendelian randomization in expression and methylation datasets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls.ConclusionsOur data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points toPARK2as a major hallmark of PD etiology in Spain.

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Genomic and multi-tissue proteomic integration for understanding the biology of disease and other complex traits

10.1101/2020.06.25.20140277 ◽

2020 ◽

Cited By ~ 1

Author(s):

Chengran Yang ◽

Fabiana G. Farias ◽

Laura Ibanez ◽

Brooke Sadler ◽

Maria Victoria Fernandez ◽

...

Keyword(s):

Gene Expression ◽

Complex Traits ◽

Drug Targets ◽

Genetic Architecture ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Protein Levels ◽

Genome Wide ◽

Novel Biomarkers ◽

Potential Drug Targets

AbstractExpression quantitative trait loci (eQTL) mapping has successfully resolved some genome-wide association study (GWAS) loci for complex traits1–6. However, there is a need for implementing additional “omic” approaches to untangle additional loci and provide a biological context for GWAS signals. We generated a detailed landscape of the genomic architecture of protein levels in multiple neurologically relevant tissues (brain, cerebrospinal fluid (CSF) and plasma), by profiling thousands of proteins in a large and well-characterized cohort. We identified 274, 127 and 32 protein quantitative loci (pQTL) for CSF, plasma and brain respectively. We demonstrated that cis-pQTL are more likely to be shared across tissues but trans-pQTL are tissue-specific. Between 78% to 87% of pQTL are not eQTL, indicating that protein levels have a different genetic architecture than gene expression. By combining our pQTL with Mendelian Randomization approaches we identified potential novel biomarkers and drug targets for neurodegenerative diseases including Alzheimer disease and frontotemporal dementia. In the context of personalized medicine, these results highlight the need for implementing additional functional genomic approaches beyond gene expression in order to understand the biology of complex traits, and to identify novel biomarkers and potential drug targets for those traits.

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Genome-wide association study reveals sex-specific genetic architecture of facial attractiveness

10.1101/339226 ◽

2018 ◽

Author(s):

Bowen Hu ◽

Ning Shen ◽

James J. Li ◽

Hyunseung Kang ◽

Jinkuk Hong ◽

...

Keyword(s):

Association Study ◽

Genetic Architecture ◽

Genetic Basis ◽

Genome Wide Association Study ◽

Genetic Correlations ◽

Facial Attractiveness ◽

Genome Wide Association ◽

Hormone Synthesis ◽

Genome Wide ◽

A Genome

AbstractFacial attractiveness is a complex human trait of great interest in both academia and industry. Literature on sociological and phenotypic factors associated with facial attractiveness is rich, but its genetic basis is poorly understood. In this paper, we conducted a genome-wide association study to discover genetic variants associated with facial attractiveness using 3,928 samples in the Wisconsin Longitudinal Study. We identified two genome-wide significant loci and highlighted a handful of candidate genes, many of which are specifically expressed in human tissues involved in reproduction and hormone synthesis. Additionally, facial attractiveness showed strong and negative genetic correlations with BMI in females and with blood lipids in males. Our analysis also suggested sex-specific selection pressure on variants associated with lower male attractiveness. These results revealed sex-specific genetic architecture of facial attractiveness and provided fundamental new insights into its genetic basis.

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GWIS: Genome Wide Inferred Statistics for non-linear functions of multiple phenotypes

10.1101/035329 ◽

2015 ◽

Cited By ~ 1

Author(s):

Harold Nieuwboer ◽

Rene Pool ◽

Conor V Dolan ◽

Dorret I Boomsma ◽

Michel G Nivard

Keyword(s):

Genetic Architecture ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Linear Functions ◽

Standard Errors ◽

Summary Statistics ◽

Polygenic Risk ◽

Multiple Phenotypes ◽

Genome Wide ◽

Risk Scoring

Here we present a method of genome wide inferred study (GWIS) that provides an approximation of genome wide association study (GWAS) summary statistics for a variable that is a function of phenotypes for which GWAS summary statistics, phenotypic means and covariances are available. GWIS can be performed regardless of sample overlap between the GWAS of the phenotypes on which the function depends. As GWIS provides association estimates and their standard errors for each SNP, GWIS can form the basis for polygenic risk scoring, LD score regression, Mendelian randomization studies, biological annotation and other analyses. Here, we replicate a body mass index (BMI) GWAS using GWIS based on a height GWAS and a weight GWAS. We proceed to use a GWIS to further our understanding of the genetic architecture of schizophrenia and bipolar disorder.

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Novel insights into the common heritable liability to addiction: a multivariate genome-wide association study

10.1101/2021.11.19.21266548 ◽

2021 ◽

Author(s):

Tabea Schoeler ◽

Jessie Baldwin ◽

Andrea Allegrini ◽

Wikus Barkhuizen ◽

Andrew McQuillin ◽

...

Keyword(s):

Association Study ◽

Genetic Architecture ◽

Genome Wide Association Study ◽

Genetic Correlations ◽

Brain Regions ◽

Genome Wide Association ◽

Drug Reinforcement ◽

Heroin Use ◽

Genome Wide ◽

The Common

Addiction to nicotine, alcohol and cannabis commonly co-occurs, which is thought to partly stem from a common heritable liability. To elucidate its genetic architecture, we modelled the common liability to addiction, inferred from genetic correlations among six measures of dependence and frequency of use of nicotine, alcohol and cannabis. Forty-two genetic variants were identified in the multivariate genome-wide association study on the common liability to addiction, of which 67% were novel and not associated with the six phenotypes. Mapped genes highlighted the role of dopamine (e.g., dopamine D2 gene), and showed enrichment for a several components of the central nervous systems (e.g., mesocorticolimbic brain regions) and molecular pathways (dopaminergic, glutamatergic, GABAergic) that are thought to modulate drug reinforcement. Genetic correlations with other traits were most prominent for reward-related behaviours (e.g., risk-taking, cocaine and heroin use) and mood (e.g., depression, insomnia). These genome-wide results triangulate and expand previous preclinical and human studies focusing on the neurobiological substrates of addiction, and help to elucidate the common genetic architecture underlying addiction.

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Lack of evidence for genetic association of saposins A, B, C and D with Parkinson disease

10.1101/2020.05.31.20061010 ◽

2020 ◽

Author(s):

Yuri Ludwig Sosero ◽

Sara Bandres Ciga ◽

Sharon Hassin ◽

Roy N. Alcalay ◽

Ziv Gan-Or

Keyword(s):

Parkinson Disease ◽

Genetic Association ◽

Genome Wide Association Study ◽

Disease Risk ◽

Age At Onset ◽

The Other ◽

Minor Role ◽

Common Variants ◽

Lysosomal Storage ◽

Genome Wide

The PSAP gene encodes prosaposin, which is later cleaved into four active saposins: saposin A, B, C and D. Mutations in these enzymes have been linked to specific lysosomal storage disorders. Recently, a genetic association between mutations in saposin D and Parkinson disease (PD) has been reported. To further examine whether variants in saposin D or the other saposins could be associated with Parkinson s disease, we performed Optimized Sequence Kernel Association Test (SKAT-O) in 4,132 Parkinson s disease patients and 4,470 controls. Furthermore, we analyzed data from a PD Genome Wide Association Study (GWAS) to examine the association of common variants in the PSAP locus with Parkinson s disease risk (analysis on 56,308 patients) and age at onset (analysis on 28,568 patients). We did not find any statistically significant associations between neither rare nor common variants in saposin D, nor any of the other saposins, and PD risk or onset. These results suggest that PSAP variants play either a very minor role, or more likely, no role, in PD.

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Using multiple Mendelian randomization approaches and genetic correlations to understand obesity, urate, and gout

Scientific Reports ◽

10.1038/s41598-021-97410-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Charleen D. Adams ◽

Brian B. Boutwell

Keyword(s):

Observational Studies ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Low Density Lipoprotein ◽

Genetic Correlations ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Low Density Lipoprotein Cholesterol ◽

Genome Wide ◽

Genetically Determined

AbstractObservational studies suggest relationships between obesity, urate, and gout but are possibly confounded. We assessed whether genetically determined obesity, higher urate (and related traits), and gout were causal using multiple Mendelian randomization (MR) approaches and linkage disequilibrium score regression for genetic correlations (rg). For data, we used genome-wide association study summary statistics available through MR-Base. We observed that obesity increased urate (beta = 0.127; 95% CI = 0.098, 0.157; P-value = 1.2E−17; rg = 0.25 [P-value = 0.001]) and triglycerides (beta = 0.082; 95% CI = 0.065, 0.099; P-value = 1.2E−21; rg = 0.23 [P-value = 8.8E−12]) and decreased high-density lipoprotein cholesterol (HDL) (beta = − 0.083; 95% CI = − 0.101, − 0.065; P-value = 2.5E−19; rg = − 0.28; [P-value = 5.2E−24]). Higher triglycerides increased urate (beta = 0.198; 95% CI = 0.146, 0.251; P-value = 8.9E−14; rg = 0.29 [P-value = 0.001]) and higher HDL decreased urate (beta = − 0.109; 95% CI = − 0.148, − 0.071; P-value = 2.7E− 08; rg = − 0.21 [P-value = 9.8E−05]). Higher urate (OR = 1.030; 95% CI = 1.028, 1.032; P-value = 1.1E−130; rg = 0.89 [P-value = 1.7E−55]) and obesity caused gout (OR = 1.003; 95% CI = 1.001, 1.004; P-value = 1.3E−04; rg = 0.23 [P-value = 2.7E−05]). Obesity on gout with urate as a mediator revealed all the effect of obesity on gout occurred through urate. Obesity on low-density lipoprotein cholesterol (LDL) was null (beta = −0.011; 95% CI = −0.030, 0.008; P-value = 2.6E−01; rg = 0.03 [P-value = 0.369]). A multivariable MR of obesity, HDL, and triglycerides on urate showed obesity influenced urate when accounting for HDL and triglycerides. Obesity’s impact on urate was exacerbated by it decreasing HDL.

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Genetic risk scores and hallucinations in patients with Parkinson disease

Neurology Genetics ◽

10.1212/nxg.0000000000000492 ◽

2020 ◽

Vol 6 (5) ◽

pp. e492 ◽

Cited By ~ 1

Author(s):

Cynthia D.J. Kusters ◽

Kimberly C. Paul ◽

Aline Duarte Folle ◽

Adrienne M. Keener ◽

Jeff M. Bronstein ◽

...

Keyword(s):

Parkinson Disease ◽

Genetic Risk ◽

Genetic Architecture ◽

Disease Duration ◽

Genome Wide Association Study ◽

Population Based ◽

Negative Control ◽

European Ancestry ◽

Risk Scores ◽

Genome Wide

ObjectiveWe examine the hypothesized overlap of genetic architecture for Alzheimer disease (AD), schizophrenia (SZ), and Parkinson disease (PD) through the use of polygenic risk scores (PRSs) with the occurrence of hallucinations in PD.MethodsWe used 2 population-based studies (ParkWest, Norway, and Parkinson's Environment and Gene, USA) providing us with 399 patients with PD with European ancestry and a PD diagnosis after age 55 years to assess the associations between 4 PRSs and hallucinations after 5 years of mean disease duration. Based on the existing genome-wide association study of other large consortia, 4 PRSs were created: one each using AD, SZ, and PD cohorts and another PRS for height, which served as a negative control.ResultsA higher prevalence of hallucinations was observed with each SD increase of the AD-PRS (odds ratio [OR]: 1.37, 95% confidence interval [CI]: 1.03–1.83). This effect was mainly driven by APOE (OR: 1.92, 95% CI: 1.14–3.22). In addition, a suggestive decrease and increase, respectively, in hallucination prevalence were observed with the SZ-PRS and the PD-PRS (OR: 0.77, 95% CI: 0.59–1.01; and OR: 1.29, 95% CI: 0.95–1.76, respectively). No association was observed with the height PRS.ConclusionsThese results suggest that mechanisms for hallucinations in PD may in part be driven by the same genetic architecture that leads to cognitive decline in AD, especially by APOE.

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Overlapping Genetic Architecture between Parkinson Disease and Melanoma

10.1101/740589 ◽

2019 ◽

Author(s):

Umber Dube ◽

Laura Ibanez ◽

John P Budde ◽

Bruno A Benitez ◽

Albert A Davis ◽

...

Keyword(s):

Gene Expression ◽

Parkinson Disease ◽

Genetic Correlation ◽

Genetic Architecture ◽

Genome Wide Association Study ◽

Case Control ◽

Epidemiologic Studies ◽

Risk Genes ◽

Genome Wide ◽

Shared Genetic

AbstractEpidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between these diseases can support epidemiologic findings and identify common risk genes and biological pathways. Here we apply polygenic, linkage disequilibrium-informed methods to the largest available case-control, genome-wide association study summary statistic data for melanoma and PD. We identify positive and significant genetic correlation (correlation: 0.17, 95% CI 0.10 to 0.24; P = 4.09 × 10-06) between melanoma and PD. We further demonstrate melanoma and PD-inferred gene expression to overlap across tissues (correlation: 0.14, 95% CI 0.06 to 0.22; P = 7.87 × 10-04), and highlight seven genes including PIEZO1, TRAPPC2L, and SOX6 as potential mediators of the genetic correlation between melanoma and PD. These findings demonstrate specific, shared genetic architecture between PD and melanoma that manifests at the level of gene expression.

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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Nature Communications ◽

10.1038/s41467-020-19366-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Vasiliki Lagou ◽

◽

Reedik Mägi ◽

Jouke- Jan Hottenga ◽

Harald Grallert ◽

...

Keyword(s):

Genome Wide Association Study ◽

Fasting Glucose ◽

Genetic Correlations ◽

Epidemiological Studies ◽

Genetic Effects ◽

Fasting Insulin ◽

Sex Dimorphism ◽

Waist To Hip Ratio ◽

Genome Wide ◽

Meta Analyses

AbstractDifferences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.

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