How understudied populations have contributed to our understanding of Alzheimer’s disease genetics

Dehghani, Nadia; Brás, José; Guerreiro, Rita

doi:10.1101/2020.06.11.146993

Cited by 3 publications

(2 citation statements)

References 100 publications

(26 reference statements)

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“…These results are consistent with the greater African genetic diversity, with recent evidence of "African" genomes demonstrating unexplored structural variation 38 and more variability in copy numbers of SMN1, SMN2 and CYP2D6 13,14 . They further highlight the need to study non-European genomes , which has yielded additional insights into Alzheimer's disease 39 , and is being expanded in PD 40 .…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of GBA using a novel algorithm for Illumina whole-genome sequence data or targeted Nanopore sequencing

Toffoli

Chen

Sedlazeck

et al. 2021

Preprint

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GBA variants cause the autosomal recessive Gaucher disease, and carriers are at increased risk of Parkinson’s disease (PD) and Lewy body dementia (LBD). The presence of a highly homologous nearby pseudogene (GBAP1) predisposes to a range of structural variants arising from either gene conversion or reciprocal recombination, the latter resulting in copy number gains or losses, complicating genetic testing and analysis. To date, short-read sequencing has not been able to fully resolve these or other variants in the key homology region, and targeted long-read sequencing has not previously resolved reciprocal recombinants. We present and validate two independent methods to resolve recombinant alleles and other variants in GBA: Gauchian, a novel bioinformatics tool for short-read, whole-genome sequencing data analysis, and Oxford Nanopore long-read sequencing after enrichment with appropriate PCR. The methods were concordant for 42 samples including 30 with a range of recombinants and GBAP1-related mutations, and Gauchian outperforms the GATK Best Practices pipeline. Applying Gauchian to Illumina sequencing of over 10,000 individuals from publicly available cohorts shows that copy number variants (CNVs) spanning GBAP1 are relatively common in Africans. CNV frequencies in PD and LBD are similar to controls, but gains may coexist with other mutations in patients, and a modifying effect cannot be excluded. Gauchian detects a higher frequency of GBA variants in LBD than PD, especially severe ones. These findings highlight the importance of accurate GBA mutation detection in these patients, which is possible by either Gauchian analysis of short-read whole genome sequencing, or targeted long-read sequencing.

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Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of GBA using a novel algorithm for Illumina whole-genome sequence data or targeted Nanopore sequencing

Toffoli

Chen

Sedlazeck

et al. 2021

Preprint

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“…In other words, we can turn the problem described above into a tool for detecting candidate causal SNPs. See for instance [69] for early results for CAD and [70] for a current overview of how crosspopulation studies have furthered the understanding of Alzheimer's Disease.…”

Section: Prediction Across Ancestry Groups Causal Variantsmentioning

confidence: 99%

From Genotype to Phenotype: polygenic prediction of complex human traits

Raben¹,

Lello²,

Widén³

et al. 2021

Preprint

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Decoding the genome confers the capability to predict characteristics of the organism (phenotype) from DNA (genotype). We describe the present status and future prospects of genomic prediction of complex traits in humans. Some highly heritable complex phenotypes such as height and other quantitative traits can already be predicted with reasonable accuracy from DNA alone. For many diseases, including important common conditions such as coronary artery disease, breast cancer, type I and II diabetes, individuals with outlier polygenic scores (e.g., top few percent) have been shown to have 5 or even 10 times higher risk than average. Several psychiatric conditions such as schizophrenia and autism also fall into this category. We discuss related topics such as the genetic architecture of complex traits, sibling validation of polygenic scores, and applications to adult health, in vitro fertilization (embryo selection), and genetic engineering.A version of this article was prepared for Genomic Prediction of Complex Traits, Springer Nature book series Methods in Molecular Biology.

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