Past demographic changes can produce distortions in patterns of genetic variation that can mimic the appearance of natural selection unless the demographic effects are explicitly removed. Here we fit ...a detailed model of human demography that incorporates divergence, migration, admixture, and changes in population size to directly sequenced data from 13,400 protein coding genes from 20 European-American and 19 African-American individuals. Based on this demographic model, we use several new and established statistical methods for identifying genes with extreme patterns of polymorphism likely to be caused by Darwinian selection, providing the first genome-wide analysis of allele frequency distributions in humans based on directly sequenced data. The tests are based on observations of excesses of high frequency-derived alleles, excesses of low frequency-derived alleles, and excesses of differences in allele frequencies between populations. We detect numerous new genes with strong evidence of selection, including a number of genes related to psychiatric and other diseases. We also show that microRNA controlled genes evolve under extremely high constraints and are more likely to undergo negative selection than other genes. Furthermore, we show that genes involved in muscle development have been subject to positive selection during recent human history. In accordance with previous studies, we find evidence for negative selection against mutations in genes associated with Mendelian disease and positive selection acting on genes associated with several complex diseases.
Association Testing of Novel Type 2 Diabetes Risk Alleles in the JAZF1 , CDC123 / CAMK1D , TSPAN8 , THADA , ADAMTS9 , and NOTCH2 Loci With Insulin Release, Insulin Sensitivity, and Obesity in a ...Population-Based Sample of 4,516 Glucose-Tolerant Middle-Aged
Danes
Niels Grarup 1 ,
Gitte Andersen 1 ,
Nikolaj T. Krarup 1 ,
Anders Albrechtsen 2 ,
Ole Schmitz 3 4 ,
Torben Jørgensen 5 ,
Knut Borch-Johnsen 1 5 6 ,
Torben Hansen 1 and
Oluf Pedersen 1 6
1 Steno Diabetes Center, Copenhagen, Denmark
2 Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark
3 Department of Endocrinology and Diabetes, Aarhus University Hospital, Aarhus, Denmark
4 Department of Clinical Pharmacology, University of Aarhus, Aarhus, Denmark
5 Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark
6 Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark
Corresponding author: Niels Grarup, ngrp{at}steno.dk
Abstract
OBJECTIVE— We evaluated the impact on diabetes-related intermediary traits of common novel type 2 diabetes–associated variants in the
JAZF1 (rs864745), CDC123 / CAMK1D (rs12779790), TSPAN8 (rs7961581), THADA (rs7578597), AD AMTS9 (rs4607103), and NOTCH2 (rs10923931) loci, which were recently identified by meta-analysis of genome-wide association data.
RESEARCH DESIGN AND METHODS— We genotyped the six variants in 4,516 middle-aged glucose-tolerant individuals of the population-based Inter99 cohort who
were all characterized by an oral glucose tolerance test (OGTT).
RESULTS— Homozygous carriers of the minor diabetes risk G-allele of the CDC123 / CAMK1D rs12779790 showed an 18% decrease in insulinogenic index (95% CI 10–27%; P = 4 × 10 −5 ), an 18% decrease in corrected insulin response (CIR) (8.1–29%; P = 4 × 10 −4 ), and a 13% decrease in the ratio of area under the serum-insulin and plasma-glucose curves during an OGTT (AUC-insulin/AUC-glucose)
(5.8–20%; P = 4 × 10 −4 ). Carriers of the diabetes-associated T-allele of JAZF1 rs864745 had an allele-dependent 3% decrease in BIGTT-AIR (0.9–4.3%; P = 0.003). Furthermore, the diabetes-associated C-allele of TSPAN8 rs7961581 associated with decreased levels of CIR (4.5% 0.5–8.4; P = 0.03), of AUC-insulin/AUC-glucose ratio (3.9% 1.2–6.7; P = 0.005), and of the insulinogenic index (5.2% 1.9–8.6; P = 0.002). No association with traits of insulin release or insulin action was observed for the THADA , ADAMTS9 , or NOTCH2 variants.
CONCLUSIONS— If replicated, our data suggest that type 2 diabetes at-risk alleles in the JAZF1 , CDC123 / CAMK1D , and TSPAN8 loci associate with various OGTT-based surrogate measures of insulin release, emphasizing the contribution of abnormal pancreatic
β-cell function in the pathogenesis of type 2 diabetes.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 20 June 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted June 16, 2008.
Received March 30, 2008.
DIABETES
Aims/hypothesis
In a recent study using a standard additive genetic model, we identified a
TBC1D4
loss-of-function variant with a large recessive impact on risk of type 2 diabetes in Greenlanders. ...The aim of the current study was to identify additional genetic variation underlying type 2 diabetes using a recessive genetic model, thereby increasing the power to detect variants with recessive effects.
Methods
We investigated three cohorts of Greenlanders (B99,
n
= 1401; IHIT,
n
= 3115; and BBH,
n
= 547), which were genotyped using Illumina MetaboChip. Of the 4674 genotyped individuals passing quality control, 4648 had phenotype data available, and type 2 diabetes association analyses were performed for 317 individuals with type 2 diabetes and 2631 participants with normal glucose tolerance. Statistical association analyses were performed using a linear mixed model.
Results
Using a recessive genetic model, we identified two novel loci associated with type 2 diabetes in Greenlanders, namely rs870992 in
ITGA1
on chromosome 5 (OR 2.79,
p
= 1.8 × 10
−8
), and rs16993330 upstream of
LARGE1
on chromosome 22 (OR 3.52,
p
= 1.3 × 10
−7
). The
LARGE1
variant did not reach the conventional threshold for genome-wide significance (
p
< 5 × 10
−8
) but did withstand a study-wide Bonferroni-corrected significance threshold. Both variants were common in Greenlanders, with minor allele frequencies of 23% and 16%, respectively, and were estimated to have large recessive effects on risk of type 2 diabetes in Greenlanders, compared with additively inherited variants previously observed in European populations.
Conclusions/interpretation
We demonstrate the value of using a recessive genetic model in a historically small and isolated population to identify genetic risk variants. Our findings give new insights into the genetic architecture of type 2 diabetes, and further support the existence of high-effect genetic risk factors of potential clinical relevance, particularly in isolated populations.
Data availability
The Greenlandic MetaboChip-genotype data are available at European Genome-Phenome Archive (EGA;
https://ega-archive.org/
) under the accession EGAS00001002641.
Testing for deviations from Hardy–Weinberg equilibrium (HWE) is a common practice for quality control in genetic studies. Variable sites violating HWE may be identified as technical errors in the ...sequencing or genotyping process, or they may be of particular evolutionary interest. Large‐scale genetic studies based on next‐generation sequencing (NGS) methods have become more prevalent as cost is decreasing but these methods are still associated with statistical uncertainty. The large‐scale studies usually consist of samples from diverse ancestries that make the existence of some degree of population structure almost inevitable. Precautions are therefore needed when analysing these data set, as population structure causes deviations from HWE. Here we propose a method that takes population structure into account in the testing for HWE, such that other factors causing deviations from HWE can be detected. We show the effectiveness of PCAngsd in low‐depth NGS data, as well as in genotype data, for both simulated and real data set, where the use of genotype likelihoods enables us to model the uncertainty.
Pathogenic germline mutations in the folliculin (FLCN) tumor suppressor gene predispose to Birt-Hogg-Dubé (BHD) syndrome, a rare disease characterized by the development of cutaneous hamartomas ...(fibrofolliculomas), multiple lung cysts, spontaneous pneumothoraces and renal cell cancer. In this study, we report the identification of 13 variants and three polymorphisms in the FLCN gene in 143 Danish patients or families with suspected BHD syndrome. Functional mini-gene splicing analysis revealed that two intronic variants (c.1062+2T>G and c.1177-5_1177-3del) introduced splicing aberrations. Eleven families exhibited the c.1062+2T>G mutation. Combined single nucleotide polymorphism array-haplotype analysis showed that these families share a 3-Mb genomic fragment containing the FLCN gene, revealing that the c.1062+2T>G mutation is a Danish founder mutation. On the basis of in silico prediction and functional splicing assays, we classify the 16 identified variants in the FLCN gene as follows: nine as pathogenic, one as likely pathogenic, three as likely benign and three as polymorphisms. In conclusion, the study describes the FLCN mutation spectrum in Danish BHD patients, and contributes to a better understanding of BHD syndrome and management of BHD patients.
Fatty acids (FAs) are involved in cellular processes important for normal body function, and perturbation of FA balance has been linked to metabolic disturbances, including type 2 diabetes. An ...individual's level of FAs is affected by diet, lifestyle, and genetic variation. We aimed to improve the understanding of the mechanisms and pathways involved in regulation of FA tissue levels, by identifying genetic loci associated with inter-individual differences in erythrocyte membrane FA levels. We assessed the levels of 22 FAs in the phospholipid fraction of erythrocyte membranes from 2,626 Greenlanders in relation to single nucleotide polymorphisms genotyped on the MetaboChip or imputed. We identified six independent association signals. Novel loci were identified on chromosomes 5 and 11 showing strongest association with oleic acid (rs76430747 in ACSL6, beta (SE): -0.386% (0.034), p = 1.8x10-28) and docosahexaenoic acid (rs6035106 in DTD1, 0.137% (0.025), p = 6.4x10-8), respectively. For a missense variant (rs80356779) in CPT1A, we identified a number of novel FA associations, the strongest with 11-eicosenoic acid (0.473% (0.035), p = 2.6x10-38), and for variants in FADS2 (rs174570), LPCAT3 (rs2110073), and CERS4 (rs11881630) we replicated known FA associations. Moreover, we observed metabolic implications of the ACSL6 (rs76430747) and CPT1A (rs80356779) variants, which both were associated with altered HbA1c (0.051% (0.013), p = 5.6x10-6 and -0.034% (0.016), p = 3.1x10-4, respectively). The latter variant was also associated with reduced insulin resistance (HOMA-IR, -0.193 (0.050), p = 3.8x10-6), as well as measures of smaller body size, including weight (-2.676 kg (0.523), p = 2.4x10-7), lean mass (-1.200 kg (0.271), p = 1.7x10-6), height (-0.966 cm (0.230), p = 2.0x10-5), and BMI (-0.638 kg/m2 (0.181), p = 2.8x10-4). In conclusion, we have identified novel genetic determinants of FA composition in phospholipids in erythrocyte membranes, and have shown examples of links between genetic variants associated with altered FA membrane levels and changes in metabolic traits.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pairwise relatedness plays an important role in a range of genetic research fields. However, currently only few estimators exist for individuals that are admixed, i.e. have ancestry from more than ...one population, and these estimators fail in some situations.
We present a new software tool, RelateAdmix, for obtaining maximum likelihood estimates of pairwise relatedness from genetic data between admixed individuals. We show using simulated data that it gives rise to better estimates than three state-of-the-art software tools, REAP, KING and Plink, while still being fast enough to be applicable to large datasets.
The software tool, implemented in C and R, is freely available from www.popgen.dk/software.
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