Whole-Exome Sequencing of 2,000 Danish Individuals and the Role of Rare Coding Variants in Type 2 Diabetes

Lohmueller, Kirk E.; Sparsø, Thomas; Li, Qibin; Andersson, Ehm A.; Korneliussen, Thorfinn; Albrechtsen, Anders; Banasik, Karina; Grarup, Niels; Hallgrímsdóttir, Ingileif B.; Kiil, Kristoffer; Kilpeläinen, Tuomas O.; Krarup, Nikolaj T.; Pers, Tune H.; Sánchez, Gastón; Hu, Youna; DeGiorgio, Michael; Jørgensen, Torben; Sandbæk, Annelli; Lauritzen, Torsten; Brunak, Søren; Kristiansen, Karsten; Li, Yingrui; Hansen, Torben; Wang, Jun; Nielsen, Rasmus; Pedersen, Oluf

doi:10.1016/j.ajhg.2014.02.002

Cited by 46 publications

(68 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We also assessed the allele frequency data of identified variants derived from an available 'control' exome data set provided by NHLBI Exome Variant Server (EVS, http://evs.gs.washington.edu/EVS/) and the Danish exome study. 24 For the RPE65 variants deposited in the RPE65 LOVD, we also assessed their prevalence using the Exome Aggregate Consortium (ExAC) database (http:// exac.broadinstitute.org). Five computational prediction programs, SpliceSite finder-like, 25 MaxEntScan, 26 NNSPLICE, 27 Gene Splicer 28 and Human Splicing Finder 29 were used to determine the pathogenic effect of noncanonical splice variants.…”

Section: Pathogenicity Interpretation Of Sequence Variantsmentioning

confidence: 99%

Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark

et al. 2015

View full text Add to dashboard Cite

Leber congenital amaurosis (LCA) represents the most severe form of inherited retinal dystrophies with an onset during the first year of life. Currently, 21 genes are known to be associated with LCA and recurrent mutations have been observed in AIPL1, CEP290, CRB1 and GUCY2D. In addition, sequence analysis of LRAT and RPE65 may be important in view of treatments that are emerging for patients carrying variants in these genes. Screening of the aforementioned variants and genes was performed in 64 Danish LCA probands. Upon the identification of heterozygous variants, Sanger sequencing was performed of the relevant genes to identify the second allele. In combination with prior arrayed primer extension analysis, this led to the identification of two variants in 42 of 86 cases (49%). Remarkably, biallelic RPE65 variants were identified in 16% of the cases, and one novel variant, p.(D110G), was found in seven RPE65 alleles. We also collected all previously published RPE65 variants, identified in 914 alleles of 539 patients with LCA or early-onset retinitis pigmentosa, and deposited them in the RPE65 Leiden Open Variation Database (LOVD). The in silico pathogenicity assessment of the missense and noncanonical splice site variants, as well as an analysis of their frequency in~60 000 control individuals, rendered 864 of the alleles to affect function or probably affect function. This comprehensive database can now be used to select patients eligible for gene augmentation or retinoid supplementation therapies.

show abstract

Section: Pathogenicity Interpretation Of Sequence Variantsmentioning

confidence: 99%

Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Developments in genotyping and sequencing technologies have further enabled the study of lowfrequency and rare genetic variation [18,21,22]. However, given that most loci contribute only modest effects in the studied populations, the sample sizes required to obtain sufficient statistical power are enormous, reaching >500,000 European or Asian individuals.…”

Section: Gwas In Population Isolatesmentioning

confidence: 99%

Diabetes in Population Isolates: Lessons from Greenland

Grarup¹,

Moltke²,

Albrechtsen³

et al. 2015

Rev Diabet Stud

Self Cite

View full text Add to dashboard Cite

■ AbstractType 2 diabetes (T2D) is an increasing health problem worldwide with particularly high occurrence in specific subpopulations and ancestry groups. The high prevalence of T2D is caused both by changes in lifestyle and genetic predisposition. A large number of studies have sought to identify the genetic determinants of T2D in large, open populations such as Europeans and Asians. However, studies of T2D in population isolates are gaining attention as they provide several advantages over open populations in genetic disease studies, including increased linkage disequilibrium, homogeneous environmental exposure, and increased allele frequency. We recently performed a study in the small, historically isolated Greenlandic population, in which the prevalence of T2D has increased to more than 10%. In this study, we identified a common nonsense variant in TBC1D4, which has a population-wide impact on glucose-stimulated plasma glucose, serum insulin levels, and T2D. The variant defines a specific subtype of non-autoimmune diabetes characterized by decreased post-prandial glucose uptake and muscular insulin resistance. These and other recent findings in population isolates illustrate the value of performing medical genetic studies in genetically isolated populations. In this review, we describe some of the advantages of performing genetic studies of T2D and related cardio-metabolic traits in a population isolate like the Greenlandic, and we discuss potentials and perspectives for future research into T2D in this population.

show abstract

“…More work is required to estimate the amount of pleiotropic selection on trait-altering variation before we can assert that rare alleles may play a substantial role in shaping trait variation for many important human phenotypes. Genome-wide rare variant association studies (RVAS) have often been used in an attempt to bound the variance explained by rare alleles for complex traits (Lohmueller et al 2013;Holmen et al 2014;Igartua et al 2015). In this study design, researchers scan the genome (or exome) for rare causal alleles with one or more RVATs and report that rare alleles are unlikely to be a driver of variance in the trait if no signal (or very few signals) are found.…”

Section: Cold Spring Harbor Laboratory Press On May 7 2018 -Publishementioning

confidence: 99%

“…Although studies of complex phenotypes have often suggested that most genetic variance is attributable to common variants of weak effect (Yang et al 2010;Lohmueller et al 2013;Gaugler et al 2014;Igartua et al 2015), recent work has implicated rare variants as a non-negligible source of variance for traits such as height (Yang et al 2015) and prostate cancer (Mancuso et al 2015). With many large-scale sequencing studies underway in an effort to discover the heritable basis of complex traits, it is imperative that geneticists be able to robustly identify association signals in this deluge of noisy data (Maher et al 2012).…”

mentioning

confidence: 99%

Selection and explosive growth alter genetic architecture and hamper the detection of causal rare variants

Uricchio

Zaitlen

et al. 2016

Genome Res.

View full text Add to dashboard Cite

The role of rare alleles in complex phenotypes has been hotly debated, but most rare variant association tests (RVATs) do not account for the evolutionary forces that affect genetic architecture. Here, we use simulation and numerical algorithms to show that explosive population growth, as experienced by human populations, can dramatically increase the impact of very rare alleles on trait variance. We then assess the ability of RVATs to detect causal loci using simulations and human RNA-seq data. Surprisingly, we find that statistical performance is worst for phenotypes in which genetic variance is due mainly to rare alleles, and explosive population growth decreases power. Although many studies have attempted to identify causal rare variants, few have reported novel associations. This has sometimes been interpreted to mean that rare variants make negligible contributions to complex trait heritability. Our work shows that RVATs are not robust to realistic human evolutionary forces, so general conclusions about the impact of rare variants on complex traits may be premature.

show abstract

Whole-Exome Sequencing of 2,000 Danish Individuals and the Role of Rare Coding Variants in Type 2 Diabetes

Cited by 46 publications

References 0 publications

Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark

Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark

Diabetes in Population Isolates: Lessons from Greenland

Selection and explosive growth alter genetic architecture and hamper the detection of causal rare variants

Contact Info

Product

Resources

About