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  • 1.
    Boström, Adrian E.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Mwinyi, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Voisin, Sarah
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Wu, Wenting
    Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA..
    Schultes, Bernd
    eSwiss Med & Surg Ctr, St Gallen, Switzerland..
    Zhang, Kang
    Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA..
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Longitudinal genome-wide methylation study of Roux-en-Y gastric bypass patients reveals novel CpG sites associated with essential hypertension2016Ingår i: BMC Medical Genomics, ISSN 1755-8794, E-ISSN 1755-8794, Vol. 9, artikel-id 20Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Essential hypertension is a significant risk factor for cardiovascular diseases. Emerging research suggests a role of DNA methylation in blood pressure physiology. We aimed to investigate epigenetic associations of promoter related CpG sites to essential hypertension in a genome-wide methylation approach. Methods: The genome-wide methylation pattern in whole blood was measured in 11 obese patients before and six months after Roux-en-Y gastric bypass surgery using the Illumina 450 k beadchip. CpG sites located within 1500 bp of the transcriptional start site of adjacent genes were included in our study, resulting in 124 199 probes investigated in the subsequent analysis. Percent changes in methylation states and SBP measured before and six months after surgery were calculated. These parameters were correlated to each other using the Spearman's rank correlation method (Edgeworth series approximation). To further investigate the detected relationship between candidate CpG sites and systolic blood pressure levels, binary logistic regression analyses were performed in a larger and independent cohort of 539 individuals aged 19-101 years to elucidate a relationship between EH and the methylation state in candidate CpG sites. Results: We identified 24 promoter associated CpG sites that correlated with change in SBP after RYGB surgery (p < 10-16). Two of these CpG loci (cg00875989, cg09134341) were significantly hypomethylated in dependency of EH (p < 10-03). These results were independent of age, BMI, ethnicity and sex. Conclusions: The identification of these novel CpG sites may contribute to a further understanding of the epigenetic regulatory mechanisms underlying the development of essential hypertension.

  • 2.
    Bysani, Madhu Sudhan Reddy
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wallerman, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bornelöv, Susanne
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Zatloukal, Kurt
    Komorowski, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wadelius, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    ChIP-seq in steatohepatitis and normal liver tissue identifies candidate disease mechanisms related to progression to cancer2013Ingår i: BMC Medical Genomics, ISSN 1755-8794, E-ISSN 1755-8794, Vol. 6, s. 50-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Steatohepatitis occurs in alcoholic liver disease and may progress to liver cirrhosis and hepatocellular carcinoma. Its molecular pathogenesis is to a large degree unknown. Histone modifications play a key role in transcriptional regulations as marks for silencing and activation of gene expression and as marks for functional elements. Many transcription factors (TFs) are crucial for the control of the genes involved in metabolism, and abnormality in their function may lead to disease. Methods: We performed ChIP-seq of the histone modifications H3K4me1, H3K4me3 and H3K27ac and a candidate transcription factor (USF1) in liver tissue from patients with steatohepatitis and normal livers and correlated results to mRNA-expression and genotypes. Results: We found several regions that are differentially enriched for histone modifications between disease and normal tissue, and qRT-PCR results indicated that the expression of the tested genes strongly correlated with differential enrichment of histone modifications but is independent of USF1 enrichment. By gene ontology analysis of differentially modified genes we found many disease associated genes, some of which had previously been implicated in the etiology of steatohepatitis. Importantly, the genes associated to the strongest histone peaks in the patient were over-represented in cancer specific pathways suggesting that the tissue was on a path to develop to cancer, a common complication to the disease. We also found several novel SNPs and GWAS catalogue SNPs that are candidates to be functional and therefore needs further study. Conclusion: In summary we find that analysis of chromatin features in tissue samples provides insight into disease mechanisms.

  • 3.
    Glicksberg, Benjamin S.
    et al.
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Inst Next Generat Healthcare, One Gustave L Levy Pl, New York, NY 10029 USA;Univ Calif San Francisco, Bakar Computat Hlth Sci Inst, San Francisco, CA 94158 USA.
    Amadori, Letizia
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Cardiovasc Inst, One Gustave L Levy Pl, New York, NY 10029 USA.
    Akers, Nicholas K.
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA.
    Sukhavasi, Katyayani
    Univ Tartu, Inst Biomed & Translat Med, Dept Pathophysiol, Ravila 19, EE-50411 Tartu, Estonia.
    Franzen, Oscar
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Clin Gene Networks AB, Jungfrugatan 10, S-11444 Stockholm, Sweden;Karolinska Inst, Integrated Cardio Metab Ctr, Dept Med, S-14157 Huddinge, Sweden.
    Li, Li
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Inst Next Generat Healthcare, One Gustave L Levy Pl, New York, NY 10029 USA.
    Belbin, Gillian M.
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, One Gustave L Levy Pl, New York, NY 10029 USA.
    Akers, Kristin L.
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Sema4, Stamford, CT 06902 USA.
    Shameer, Khader
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Inst Next Generat Healthcare, One Gustave L Levy Pl, New York, NY 10029 USA.
    Badgeley, Marcus A.
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Inst Next Generat Healthcare, One Gustave L Levy Pl, New York, NY 10029 USA.
    Johnson, Kipp W.
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Inst Next Generat Healthcare, One Gustave L Levy Pl, New York, NY 10029 USA.
    Readhead, Ben
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Inst Next Generat Healthcare, One Gustave L Levy Pl, New York, NY 10029 USA.
    Darrow, Bruce J.
    Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Cardiovasc Inst, One Gustave L Levy Pl, New York, NY 10029 USA.
    Kenny, Eimear E.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Dept Prevent Med, One Gustave L Levy Pl, New York, NY 10029 USA.
    Betsholtz, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Ermel, Raili
    Tartu Univ Hosp, Dept Cardiac Surg, 1a Ludwig Puusepa St, EE-50406 Tartu, Estonia.
    Skogsberg, Josefin
    Karolinska Univ Sjukhuset Huddinge, Integrated Cardio Metab Ctr, Karolinska Inst, Dept Med, S-14186 Stockholm, Sweden.
    Ruusalepp, Arno
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Clin Gene Networks AB, Jungfrugatan 10, S-11444 Stockholm, Sweden.
    Schadt, Eric E.
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Inst Next Generat Healthcare, One Gustave L Levy Pl, New York, NY 10029 USA;Clin Gene Networks AB, Jungfrugatan 10, S-11444 Stockholm, Sweden;Sema4, Stamford, CT 06902 USA.
    Dudleyt, Joel T.
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Inst Next Generat Healthcare, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Dept Hlth Policy & Res, One Gustave L Levy Pl, New York, NY 10029 USA.
    Ren, Hongxia
    Indiana Univ, Herman B Wells Ctr Pediat Res, Ctr Diabet & Metab Dis, Dept Pediat,Stark Neurosci Res Inst, 635 Barnhill Dr,MS2049, Indianapolis, IN 46202 USA.
    Kovacic, Jason C.
    Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Cardiovasc Inst, One Gustave L Levy Pl, New York, NY 10029 USA.
    Giannarelli, Chiara
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, One Gustave L Levy Pl, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Cardiovasc Inst, One Gustave L Levy Pl, New York, NY 10029 USA.
    Liu, Shuyu D.
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Sema4, Stamford, CT 06902 USA.
    Bjorkegren, Johan L. M.
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Univ Tartu, Inst Biomed & Translat Med, Dept Pathophysiol, Ravila 19, EE-50411 Tartu, Estonia;Clin Gene Networks AB, Jungfrugatan 10, S-11444 Stockholm, Sweden;Karolinska Univ Sjukhuset Huddinge, Integrated Cardio Metab Ctr, Karolinska Inst, Dept Med, S-14186 Stockholm, Sweden.
    Chen, Rong
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA;Sema4, Stamford, CT 06902 USA.
    Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits2019Ingår i: BMC Medical Genomics, ISSN 1755-8794, E-ISSN 1755-8794, Vol. 12, artikel-id 108Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene.

    Results

    We identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight.

    Conclusion

    In sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.

  • 4.
    Hedman, Åsa K.
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Zilmer, Mihkel
    Univ Tartu, Inst Biomed & Translat Med, Dept Biochem, Ctr Excellence Genom & Translat Med, Tartu, Estonia..
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    DNA methylation patterns associated with oxidative stress in an ageing population2016Ingår i: BMC Medical Genomics, ISSN 1755-8794, E-ISSN 1755-8794, Vol. 9, artikel-id 72Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Oxidative stress has been related to type 2 diabetes (T2D) and cardiovascular disease (CVD), the leading global cause of death. Contributions of environmental factors such as oxidative stress on complex traits and disease may be partly mediated through changes in epigenetic marks (e.g. DNA methylation). Studies relating differential methylation with intermediate phenotypes and disease endpoints may be useful in identifying additional candidate genes and mechanisms involved in disease. Methods: To investigate the role of epigenetic variation in oxidative stress marker levels and subsequent development of CVD and T2D, we performed analyses of genome-wide DNA methylation in blood, ten markers of oxidative stress (total glutathione [TGSH], reduced glutathione [GSH], oxidised glutathione [GSSG], GSSG to GSH ratio, homocysteine [HCY], oxidised low-density lipoprotein (oxLDL), antibodies against oxLDL [OLAB], conjugated dienes [CD], baseline conjugated dienes [BCD]-LDL and total antioxidant capacity [TAOC]) and incident disease in up to 966 age-matched individuals. Results: In total, we found 66 cytosine-guanine (CpG) sites associated with one or more oxidative stress markers (false discovery rate [FDR] <0.05). These sites were enriched in regulatory regions of the genome. Genes annotated to CpG sites showed enrichment in annotation clusters relating to phospho-metabolism and proteins with pleckstrin domains. We investigated the contribution of oxidative stress-associated CpGs to development of cardiometabolic disease. Methylation variation at CpGs in the 3'-UTR of HIST1H4D (cg08170869; histone cluster 1, H4d) and in the body of DVL1 (cg03465880; dishevelled-1) were associated with incident T2D events during 10 years of follow-up (all permutation p-values < 0.01), indicating a role of epigenetic regulation in oxidative stress processes leading to development or progression of diabetes. Methylation QTL (meQTL) analysis showed significant associations with genetic sequence variants in cis at 28 (42%) of oxidative stress phenotype-associated sites (FDR < 0.05). Integrating cis-meQTLs with genotype-phenotype associations indicated that genetic effects on oxidative stress phenotype at one locus (cg07547695; BCL2L11) may be mediated through DNA methylation. Conclusions: In conclusion, we report novel associations of DNA methylation with oxidative stress, some of which also show evidence of a relation with T2D incidence.

  • 5. Jiao, Hong
    et al.
    Arner, Peter
    Hoffstedt, Johan
    Brodin, David
    Dubern, Beatrice
    Czernichow, Sebastien
    van't Hooft, Ferdinand
    Axelsson, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pedersen, Oluf
    Hansen, Torben
    Sorensen, Thorkild I. A.
    Hebebrand, Johannes
    Kere, Juha
    Dahlman-Wright, Karin
    Hamsten, Anders
    Clement, Karine
    Dahlman, Ingrid
    Genome wide association study identifies KCNMA1 contributing to human obesity2011Ingår i: BMC Medical Genomics, ISSN 1755-8794, E-ISSN 1755-8794, Vol. 4, s. 51-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population. Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity. Methods: We performed a GWA analysis in 164 morbidly obese subjects (BMI: body mass index > 40 kg/m(2)) and 163 Swedish subjects (> 45 years) who had always been lean. The 700 SNPs displaying the strongest association with obesity in the GWA were analyzed in a second cohort comprising 460 morbidly obese subjects and 247 consistently lean Swedish adults. 23 SNPs remained significantly associated with obesity (nominal P< 0.05) and were in a step-wise manner followed up in five additional cohorts from Sweden, France, and Germany together comprising 4214 obese and 5417 lean or population-based control individuals. Three samples, n = 4133, were used to investigate the population-based associations with BMI. Gene expression in abdominal subcutaneous adipose tissue in relation to obesity was investigated for 14 adults. Results: Potassium channel, calcium activated, large conductance, subfamily M, alpha member (KCNMA1) rs2116830*G and BDNF rs988712*G were associated with obesity in five of six investigated case-control cohorts. In meta-analysis of 4838 obese and 5827 control subjects we obtained genome-wide significant allelic association with obesity for KCNMA1 rs2116830*G with P = 2.82 x 10(-10) and an odds ratio (OR) based on cases vs controls of 1.26 [95% C. I. 1.12-1.41] and for BDNF rs988712*G with P = 5.2 x 10(-17) and an OR of 1.36 [95% C. I. 1.20-1.55]. KCNMA1 rs2116830*G was not associated with BMI in the population-based samples. Adipose tissue (P = 0.0001) and fat cell (P = 0.04) expression of KCNMA1 was increased in obesity. Conclusions: We have identified KCNMA1 as a new susceptibility locus for obesity, and confirmed the association of the BDNF locus at the genome-wide significant level.

  • 6.
    Lindholm Carlström, Eva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Halvardson, Jonatan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Etemadikhah, Mitra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wetterberg, Lennart
    Karolinska Inst, Dept Clin Neurosci CNS, K8, Stockholm, Sweden.
    Gustavson, Karl-Henrik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Feuk, Lars
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Linkage and exome analysis implicate multiple genes in non-syndromic intellectual disability in a large Swedish family2019Ingår i: BMC Medical Genomics, ISSN 1755-8794, E-ISSN 1755-8794, Vol. 12, nr 1, artikel-id 156Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Non-syndromic intellectual disability is genetically heterogeneous with dominant, recessive and complex forms of inheritance. We have performed detailed genetic studies in a large multi-generational Swedish family, including several members diagnosed with non-syndromic intellectual disability. Linkage analysis was performed on 22 family members, nine affected with mild to moderate intellectual disability and 13 unaffected family members.

    Methods

    Family members were analyzed with Affymetrix Genome-Wide Human SNP Array 6.0 and the genetic data was used to detect copy number variation and to perform genome wide linkage analysis with the SNP High Throughput Linkage analysis system and the Merlin software. For the exome sequencing, the samples were prepared using the Sure Select Human All Exon Kit (Agilent Technologies, Santa Clara, CA, USA) and sequenced using the Ion Proton (TM) System. Validation of identified variants was performed with Sanger sequencing.

    Results

    The linkage analysis results indicate that intellectual disability in this family is genetically heterogeneous, with suggestive linkage found on chromosomes 1q31-q41, 4q32-q35, 6p25 and 14q24-q31 (LOD scores of 2.4, simulated p-value of 0.000003 and a simulated genome-wide p-value of 0.06). Exome sequencing was then performed in 14 family members and 7 unrelated individuals from the same region. The analysis of coding variation revealed a pathogenic and candidate variants in different branches of the family. In three patients we find a known homozygous pathogenic mutation in the Homo sapiens solute carrier family 17 member 5 (SLC17A5), causing Salla disease. We also identify a deletion overlapping KDM3B and a duplication overlapping MAP3K4 and AGPAT4, both overlapping variants previously reported in developmental disorders.

    Conclusions

    DNA samples from the large family analyzed in this study were initially collected based on a hypothesis that affected members shared a major genetic risk factor. Our results show that a complex phenotype such as mild intellectual disability in large families from genetically isolated populations may show considerable genetic heterogeneity.

  • 7.
    Morin, Andreanne
    et al.
    McGill Univ, Dept Human Genet, Montreal, PQ, Canada.;McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Kwan, Tony
    McGill Univ, Dept Human Genet, Montreal, PQ, Canada.;McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Ge, Bing
    McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Letourneau, Louis
    McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Ban, Maria
    Univ Cambridge, Dept Clin Neurosci, Cambridge, England..
    Tandre, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Caron, Maxime
    McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Sandling, Johanna K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Carlsson, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bourque, Guillaume
    McGill Univ, Dept Human Genet, Montreal, PQ, Canada.;McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Laprise, Catherine
    Univ Quebec Chicoutimi, Dept Sci Fondamentales, Saguenay, PQ, Canada..
    Montpetit, Alexandre
    McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sawcer, Stephen J.
    Univ Cambridge, Dept Clin Neurosci, Cambridge, England..
    Lathrop, Mark G.
    McGill Univ, Dept Human Genet, Montreal, PQ, Canada.;McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Pastinen, Tomi
    McGill Univ, Dept Human Genet, Montreal, PQ, Canada.;McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Immunoseq: the identification of functionally relevant variants through targeted capture and sequencing of active regulatory regions in human immune cells2016Ingår i: BMC Medical Genomics, ISSN 1755-8794, E-ISSN 1755-8794, Vol. 9, artikel-id 59Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The observation that the genetic variants identified in genome-wide association studies (GWAS) frequently lie in non-coding regions of the genome that contain cis-regulatory elements suggests that altered gene expression underlies the development of many complex traits. In order to efficiently make a comprehensive assessment of the impact of non-coding genetic variation in immune related diseases we emulated the whole-exome sequencing paradigm and developed a custom capture panel for the known DNase I hypersensitive site (DHS) in immune cells - "Immunoseq". Results: We performed Immunoseq in 30 healthy individuals where we had existing transcriptome data from T cells. We identified a large number of novel non-coding variants in these samples. Relying on allele specific expression measurements, we also showed that our selected capture regions are enriched for functional variants that have an impact on differential allelic gene expression. The results from a replication set with 180 samples confirmed our observations. Conclusions: We show that Immunoseq is a powerful approach to detect novel rare variants in regulatory regions. We also demonstrate that these novel variants have a potential functional role in immune cells.

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