Insights into the genetic epidemiology of Crohn’s and rare diseases in the Ashkenazi Jewish population

Rivas, Manuel A.; Koskela, Jukka; Huang, Hailiang; Stevens, Christine; Avila, Brandon E.; Haritunians, Talin; Neale, Benjamin M.; Kurki, Mitja; Ganna, Andrea; Graham, Daniel B.; Gläser, Benjamin; Peter, Inga; Atzmon, Gil; Barzilai, Nir; Levine, Adam P.; Schiff, Elena; Pontikos, Nikolas; Weisburd, Ben; Karczewski, Konrad J.; Minikel, Eric Vallabh; Petersen, Britt‐Sabina; Beaugerie, Laurent; Seksik, Philippe; Cosnes, Jacques; Schreiber, Stefan; Bokemeyer, Bernd; Bethge, Johannes; Heap, Graham A.; Ahmad, Tariq; Plagnol, Vincent; Segal, Anthony W.; Targan, Stephan R.; Turner, Dan; Saavalainen, Päivi; Färkkilä, M.; Kontula, Kimmo; Pirinen, Matti; Palotie, Aarno; Brant, Steven R.; Duerr, Richard H.; Silverberg, Mark S.; Rioux, John D.; Weersma, Rinse K.; Franke, André; MacArthur, Daniel G.; Jalas, Chaim; Sokol, Harry; Xavier, Ramnik J.; Pulver, Ann E.; Cho, Judy H.; McGovern, Dermot P.; Daly, Mark J.

doi:10.1101/077180

Cited by 9 publications

(10 citation statements)

References 57 publications

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“…Additionally, large ancestry-specific PD LD reference panels, such as those for Ashkenazi Jewish patients, will help us further unravel the genetic architecture of loci such as GBA and LRRK2. This may be particularly crucial at these loci where LD patterns may be quite variable within European populations, accentuating the possible influence of LD reference series on conditional analyses in some cases 40 . Finally, our work utilized state-of-the-art QTL datasets to nominate candidate genes, but many QTL associations are hampered by both small sample size and low cis-SNP density.…”

Section: Discussionmentioning

confidence: 99%

Expanding Parkinson’s disease genetics: novel risk loci, genomic context, causal insights and heritable risk

Nalls¹,

Blauwendraat²,

Vallerga³

et al. 2018

Preprint

140

269

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We performed the largest genome-wide association study of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases, and 1.4M controls. We identified 90 independent genome-wide significant signals across 78 loci, including 38 independent risk signals in 37 novel loci. These variants explained 26-36% of the heritable risk of PD. Tests of causality within a Mendelian randomization framework identified putatively causal genes for 70 risk signals. Tissue expression enrichment analysis suggested that signatures of PD loci were heavily brain-enriched, consistent with specific neuronal cell types being implicated from single cell expression data. We found significant genetic correlations with brain volumes, smoking status, and educational attainment. In sum, these data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified.

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Section: Discussionmentioning

confidence: 99%

Expanding Parkinson’s disease genetics: novel risk loci, genomic context, causal insights and heritable risk

Nalls¹,

Blauwendraat²,

Vallerga³

et al. 2018

Preprint

140

269

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“…Tay-Sachs disease is a neurological disorder caused by recessive mutations in the HEXA gene. The disease is prevalent in the Ashkenazi Jewish population due to several founder mutations including NM 000520.5:1274_1277dup and c.1421+1G>C 23 . Using the allele frequencies from the Ashkenazi Jewish sub-population, we estimate a prevalence of 197 per million, with a 95% CI 137 to 265 per million.…”

Section: Estimating Prevalence In Well Studied Diseasesmentioning

confidence: 99%

Estimating prevalence for limb-girdle muscular dystrophy based on public sequencing databases

Liu

Pajusalu

Lake

et al. 2018

Preprint

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Purpose: Limb Girdle Muscular Dystrophies (LGMD) are a genetically heterogeneous category of autosomal inherited muscle diseases. Many genes causing LGMD have been identified, and clinical trials are beginning for treatment of some genetic subtypes. However, even with the gene-level mechanisms known, it is still difficult to get a reliable and generalizable prevalence estimation for each subtype due to the limited amount of epidemiology data and the low incidence of LGMDs. Methods: Taking advantage of recently published whole exome and genome sequencing data from the general population, we used a Bayesian method to develop a reliable disease prevalence estimator. Results: This method was applied to nine recessive LGMD subtypes. The estimated disease prevalence calculated by this method were largely comparable to published estimates from epidemiological studies, however highlighted instances of possible under-diagnosis for LGMD2B and 2L. Conclusion: The increasing size of aggregated population variant databases will allow for robust and reproducible prevalence estimates of recessive disease, which is critical for the strategic design and prioritization of clinical trials.

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“…Heterozygous functional GBA variants are one of the most common genetic risk factors for Parkinson's disease (PD) and Lewy body dementia (LBD), found in 3-20% of patients in different populations (Blauwendraat et al 2018b;Gan-Or et al 2015c;Guerreiro et al 2018;Lesage et al 2011;Rivas et al 2018). In a homozygous or compound heterozygous state, GBA variants may cause Gaucher disease, an autosomal recessive lysosomal storage disorder.…”

Section: Introductionmentioning

confidence: 99%

Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

Blauwendraat

Reed

Krohn

et al. 2019

Preprint

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Parkinson's disease (PD) is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of PD, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes.Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as PD and Lewy body dementia (LBD). These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4-to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known PD risk variants.Using multiple, large case-control datasets, totalling 217,165 individuals (22,757 PD cases, 13,431 PD proxy cases, 622 LBD cases and 180,355 controls), we identified 1,772 PD cases, 711 proxy cases and 7,624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent PD-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall PD genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S neurons were shown to have decreased Cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated PD risk and age at onset and demonstrate that variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have important implications for selection of GBA carriers for therapeutic interventions. 5

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Insights into the genetic epidemiology of Crohn’s and rare diseases in the Ashkenazi Jewish population

Cited by 9 publications

References 57 publications

Expanding Parkinson’s disease genetics: novel risk loci, genomic context, causal insights and heritable risk

Expanding Parkinson’s disease genetics: novel risk loci, genomic context, causal insights and heritable risk

Estimating prevalence for limb-girdle muscular dystrophy based on public sequencing databases

Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

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