Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease

Keller, Margaux F.; Saad, Mohamad; Brás, José; Bettella, Francesco; Nicolaou, Nayia; Simón‐Sánchez, Javier; Mittag, Florian; Büchel, Finja; Sharma, Manu; Gibbs, J. Raphael; Schulte, Claudia; Moskvina, Valentina; Dürr, Alexandra; Holmans, Peter; Kilarski, Laura L.; Guerreiro, Rita; Hernandez, Dena G.; Brice, Alexis; Ylikotila, Pauli; Stefánsson, Hreinn; Majamaa, Kari; Morris, Huw; Williams, Nigel; Gasser, Thomas; Heutink, Peter; Wood, Nicholas; Hardy, J. R.; Martínez, María Jimena; Singleton, Andrew B.; Nalls, Mike A.

doi:10.1093/hmg/ddt030

Cited by 36 publications

(49 citation statements)

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“…Generally, known GWAS –identified risk regions explain a rather small proportion of variance in the nine common cancers (nearly or <25% changes were shown when removing the SNPs within 250 kb or 500 kb of the known variants on either direction). These findings were consistent with those reported by some other studies for cancers or other traits . As compared with the much larger variance partitioned by all the common SNPs on the arrays, it indicated that additional loci with low allele frequency could be detected if we use large‐scale samples .…”

Section: Discussionsupporting

confidence: 92%

Estimation of heritability for nine common cancers using data from genome‐wide association studies in Chinese population

Dai

Shen

Wen

et al. 2016

Intl Journal of Cancer

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The familial aggregation indicated the inheritance of cancer risk. Recent genome-wide association studies (GWAS) have identified a number of common single nucleotide polymorphisms (SNPs). Following heritability analyses have shown that SNPs could explain a moderate amount of variance for different cancer phenotypes among Caucasians. However, little information was available in Chinese population. We performed a genome-wide complex trait analysis (GCTA) for common cancers at nine anatomical sites in Chinese population (14,629 cancer cases vs. 17,554 controls) and estimated the heritability of these cancers based on the common SNPs. We found that common SNPs explained certain amount of heritability with significance for all nine cancer sites: gastric cancer (20.26%), esophageal squamous cell carcinoma (19.86%), colorectal cancer (16.30%), lung cancer (15.17%), and epithelial ovarian cancer (13.31%), and a similar heritability around 10% for Hepatitis B virus (HBV)-related hepatocellular carcinoma, prostate cancer, breast cancer and nasopharyngeal carcinoma. We found that nearly or less than 25% change was shown when removing the regions expanding 250kb or 500kb up and downwards of the GWAS-reported SNPs. We also found strong linear correlations between variance partitioned by each chromosome and chromosomal length only for lung cancer (R2=0.641, P=0.001) and esophageal squamous cell cancer (R2=0.633, P=0.002), which implied us the complex heterogeneity of cancers. These results indicate polygenic genetic architecture of the nine common cancers in Chinese population. Further efforts should be made to discover the hidden heritability of different cancer types among Chinese.

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Section: Discussionsupporting

confidence: 92%

Estimation of heritability for nine common cancers using data from genome‐wide association studies in Chinese population

Dai

Shen

Wen

et al. 2016

Intl Journal of Cancer

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“…Notably, this is the first study reporting genome‐wide significance for PD GWAS loci for PD AAO. The heritability estimate of PD AAO was ∼0.11, which is much less than the heritability of PD case‐control status ∼0.27 . Our heritability estimate was lower than an estimate from a previous study in familial PD, although this was based on a relatively small data set (n = 504 families) .…”

Section: Discussioncontrasting

confidence: 82%

Parkinson's disease age at onset genome‐wide association study: Defining heritability, genetic loci, and α‐synuclein mechanisms

et al. 2019

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Background Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome‐wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. Objectives To identify the genetic determinants of PD age at onset. Methods Using genetic data of 28,568 PD cases, we performed a genome‐wide association study based on PD age at onset. Results We estimated that the heritability of PD age at onset attributed to common genetic variation was ∼0.11, lower than the overall heritability of risk for PD (∼0.27), likely, in part, because of the subjective nature of this measure. We found two genome‐wide significant association signals, one at SNCA and the other a protein‐coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni‐corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in α‐synuclein aggregation pathways. Remarkably, other well‐established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. Conclusions Overall, we have performed the largest age at onset of PD genome‐wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease‐linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. © 2019 International Parkinson and Movement Disorder Society

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“…The genetic architecture of PD is complex, and genetic variability likely accounts for a large proportion of the heterogeneity of PD, even if much of this currently remains unexplained. Conservative heritability estimates attributable to common genetic risk in PD are approximately 30%, even in sample series with only limited family history …”

Section: Recognized Risk and Protective Factors For Pd The Nature Ofmentioning

confidence: 99%

Mendelian Randomization — the Key to Understanding Aspects of Parkinson's Disease Causation?

Noyce¹,

Nalls

2015

Movement Disorders

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Parkinson's disease has multiple determinants and is associated with a wide range of exposures that appear to modify risk in traditional observational studies, including numerous lifestyle and environmental factors. Across other fields of medicine, Mendelian randomization has emerged as a powerful method to examine whether associations between exposures and disease outcomes are causal. Here we discuss the concept of Mendelian randomization, its potential relevance to Parkinson's disease, and suggest avenues through which the method could be employed to further understanding of the causal basis of Parkinson's disease. © 2015 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease

Cited by 36 publications

References 0 publications

Estimation of heritability for nine common cancers using data from genome‐wide association studies in Chinese population

Estimation of heritability for nine common cancers using data from genome‐wide association studies in Chinese population

Parkinson's disease age at onset genome‐wide association study: Defining heritability, genetic loci, and α‐synuclein mechanisms

Mendelian Randomization — the Key to Understanding Aspects of Parkinson's Disease Causation?

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