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Publications (52)

  • Elina Salmela · Hanna Renvall · Jan Kujala · [...] · Juha Kere
    [Show abstract] [Hide abstract] ABSTRACT: Several functional and morphological brain measures are partly under genetic control. The identification of direct links between neuroimaging signals and corresponding genetic factors can reveal cellular-level mechanisms behind the measured macroscopic signals and contribute to the use of imaging signals as probes of genetic function. To uncover possible genetic determinants of the most prominent brain signal oscillation, the parieto-occipital 10-Hz alpha rhythm, we measured spontaneous brain activity with magnetoencephalography in 210 healthy siblings while the subjects were resting, with eyes closed and open. The reactivity of the alpha rhythm was quantified from the difference spectra between the two conditions. We focused on three measures: peak frequency, peak amplitude, and the width of the main spectral peak. In accordance with earlier electroencephalography studies, spectral peak amplitude was highly heritable (h(2) > 0.75). Variance component-based analysis of 28000 single-nucleotide polymorphism markers revealed linkage for both the width and the amplitude of the spectral peak. The strongest linkage was detected for the width of the spectral peak over the left parieto-occipital cortex on chromosome 10 (LOD = 2.814, nominal p < 0.03). This genomic region contains several functionally plausible genes, including GRID1 and ATAD1 that regulate glutamate receptor channels mediating synaptic transmission, NRG3 with functions in brain development, and HRT7 involved in the serotonergic system and circadian rhythm. Our data suggest that the alpha oscillation is in part genetically regulated, and that it may be possible to identify its regulators by genetic analyses on a realistically modest number of samples. This article is protected by copyright. All rights reserved.
    Article · Jun 2016 · European Journal of Neuroscience
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    Fahimeh Darki · Satu Massinen · Elina Salmela · [...] · Juha Kere
    [Show abstract] [Hide abstract] ABSTRACT: The axon guidance receptor, Robo1, controls the pathfinding of callosal axons in mice. To determine whether the orthologous ROBO1 gene is involved in callosal development also in humans, we studied polymorphisms in the ROBO1 gene and variation in the white matter structure in the corpus callosum using both structural magnetic resonance imaging and diffusion tensor magnetic resonance imaging. We found that five polymorphisms in the regulatory region of ROBO1 were associated with white matter density in the posterior part of the corpus callosum pathways. One of the polymorphisms, rs7631357, was also significantly associated with the probability of connections to the parietal cortical regions. Our results demonstrate that human ROBO1 may be involved in the regulation of the structure and connectivity of posterior part of corpus callosum.
    Full-text Article · May 2016 · Brain Structure and Function
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    Dataset: S5 Table
    [Show abstract] [Hide abstract] ABSTRACT: Summary of validation data of the SCARF2 c.865_866delTC variant in Wire Fox Terriers and other related breeds. (DOCX)
    Full-text Dataset · May 2016
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    Dataset: S1 Fig
    [Show abstract] [Hide abstract] ABSTRACT: The Border Collie pedigree with tooth wear. Dogs that were whole genome sequenced are indicated by open red box. Full segregation of the FAM20C c.899C>T variant with the disease according to recessive model is indicated. (PDF)
    Full-text Dataset · May 2016
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    Dataset: S2 Table
    [Show abstract] [Hide abstract] ABSTRACT: Summary of the breeds and the number of dogs used for variant filtering in the three studies. (XLSX)
    Full-text Dataset · May 2016
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    Dataset: S4 Table
    [Show abstract] [Hide abstract] ABSTRACT: Summary of the targeted resequencing data in a developmental syndrome in Wire Fox Terriers. (DOCX)
    Full-text Dataset · May 2016
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    [Show abstract] [Hide abstract] ABSTRACT: One to two percent of all children are born with a developmental disorder requiring pediatric hospital admissions. For many such syndromes, the molecular pathogenesis remains poorly characterized. Parallel developmental disorders in other species could provide complementary models for human rare diseases by uncovering new candidate genes, improving the understanding of the molecular mechanisms and opening possibilities for therapeutic trials. We performed various experiments, e.g. combined genome-wide association and next generation sequencing, to investigate the clinico-pathological features and genetic causes of three developmental syndromes in dogs, including craniomandibular osteopathy (CMO), a previously undescribed skeletal syndrome, and dental hypomineralization, for which we identified pathogenic variants in the canine SLC37A2 (truncating splicing enhancer variant), SCARF2 (truncating 2-bp deletion) and FAM20C (missense variant) genes, respectively. CMO is a clinical equivalent to an infantile cortical hyperostosis (Caffey disease), for which SLC37A2 is a new candidate gene. SLC37A2 is a poorly characterized member of a glucose-phosphate transporter family without previous disease associations. It is expressed in many tissues, including cells of the macrophage lineage, e.g. osteoclasts, and suggests a disease mechanism, in which an impaired glucose homeostasis in osteoclasts compromises their function in the developing bone, leading to hyperostosis. Mutations in SCARF2 and FAM20C have been associated with the human van den Ende-Gupta and Raine syndromes that include numerous features similar to the affected dogs. Given the growing interest in the molecular characterization and treatment of human rare diseases, our study presents three novel physiologically relevant models for further research and therapy approaches, while providing the molecular identity for the canine conditions.
    Full-text Article · May 2016 · PLoS Genetics
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    Dataset: S3 Table
    [Show abstract] [Hide abstract] ABSTRACT: Summary of validation data of the SLC37A2 c.1332C>T variant. (DOCX)
    Full-text Dataset · May 2016
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    Dataset: S1 Table
    [Show abstract] [Hide abstract] ABSTRACT: Summary of the targeted resequencing data in CMO. (DOCX)
    Full-text Dataset · May 2016
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    Dataset: S6 Table
    [Show abstract] [Hide abstract] ABSTRACT: Summary of validation data of the FAM20C c.899C>T variant in Border Collies and other breeds. (DOCX)
    Full-text Dataset · May 2016
  • Anna Inkeri Lokki · Tea Kaartokallio · Hanna Peterson · [...] · Hannele Laivuori
    [Show abstract] [Hide abstract] ABSTRACT: Introduction: Preeclampsia is a common and partially genetic pregnancy complication characterized by hypertension and proteinuria. Association with cardiovascular disease and type 2 diabetes has been reported in 9p21 by several genome-wide association studies. It has been hypothesized that cardiometabolic diseases may share common etiology with preeclampsia. Materials and methods: We tested association with the 9p21 region to preeclampsia in the Finnish population by genotyping 23 tagging single nucleotide polymorphisms (SNPs) in 15 extended preeclampsia families and in a nationwide cohort consisting of 281 cases and 349 matched controls. Replication was conducted in additional datasets. Results: Four SNPs (rs7044859, rs496892, rs564398 and rs7865618) showed nominal association (p ≤ 0.024 uncorrected) with preeclampsia in the case-control cohort. To increase power, we genotyped two SNPs in additional 388 cases and 341 controls from the Finnish Genetics of Preeclampsia Consortium (FINNPEC) cohort. Partial replication was also attempted in a UK cohort (237 cases and 199 controls) and in 74 preeclamptic families from Australia/New Zealand. We were unable to replicate the initial association in the extended Finnish dataset or in the two international cohorts. Conclusions: Our study did not find evidence for the involvement of the 9p21 region in the risk of preeclampsia. Key messages Chromosome 9p21 is not associated with preeclampsia.
    Article · Apr 2016 · Annals of Medicine
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    [Show abstract] [Hide abstract] ABSTRACT: Lack of robust methods for establishment and expansion of pluripotent human embryonic stem (hES) cells still hampers development of cell therapy. Laminins (LN) are a family of highly cell-type specific basement membrane proteins important for cell adhesion, differentiation, migration and phenotype stability. Here we produce and isolate a human recombinant LN-521 isoform and develop a cell culture matrix containing LN-521 and E-cadherin, which both localize to stem cell niches in vivo. This matrix allows clonal derivation, clonal survival and long-term self-renewal of hES cells under completely chemically defined and xeno-free conditions without ROCK inhibitors. Neither LN-521 nor E-cadherin alone enable clonal survival of hES cells. The LN-521/E-cadherin matrix allows hES cell line derivation from blastocyst inner cell mass and single blastomere cells without a need to destroy the embryo. This method can facilitate the generation of hES cell lines for development of different cell types for regenerative medicine purposes.
    Full-text Article · Jan 2014 · Nature Communications
  • Hanna Renvall · Elina Salmela · Minna Vihla · [...] · Riitta Salmelin
    [Show abstract] [Hide abstract] ABSTRACT: Neural processes are explored through macroscopic neuroimaging and microscopic molecular measures, but the two levels remain primarily detached. The identification of direct links between the levels would facilitate use of imaging signals as probes of genetic function and, vice versa, access to molecular correlates of imaging measures. Neuroimaging patterns have been mapped for a few isolated genes, chosen based on their connection with a clinical disorder. Here we propose an approach that allows an unrestricted discovery of the genetic basis of a neuroimaging phenotype in the normal human brain. The essential components are a subject population that is composed of relatives and selection of a neuroimaging phenotype that is reproducible within an individual and similar between relatives but markedly variable across a population. Our present combined magnetoencephalography and genome-wide linkage study in 212 healthy siblings demonstrates that auditory cortical activation strength is highly heritable and, specifically in the right hemisphere, regulated oligogenically with linkages to chromosomes 2q37, 3p12, and 8q24. The identified regions delimit as candidate genes TRAPPC9, operating in neuronal differentiation, and ROBO1, regulating projections of thalamocortical axons. Identification of normal genetic variation underlying neurophysiological phenotypes offers a non-invasive platform for an in-depth, concerted capitalization of molecular and neuroimaging levels in exploring neural function.
    Article · Oct 2012 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    Dataset: Figure S8
    Elina Salmela · Tuuli Lappalainen · Jianjun Liu · [...] · Juha Kere
    [Show abstract] [Hide abstract] ABSTRACT: Linkage disequilibrium as a function of distance between markers. Median D' in overlapping 40 kb windows at 10 kb intervals is plotted for each population using 67620 marker pairs. All distributions differed significantly (p < 0.002) except Germany vs. Great Britain and Svealand vs. Götaland. Abbreviations as in Table 1. (TIF)
    Full-text Dataset · Feb 2011
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    Dataset: Figure S1
    Elina Salmela · Tuuli Lappalainen · Jianjun Liu · [...] · Juha Kere
    [Show abstract] [Hide abstract] ABSTRACT: Multidimensional scaling plots of genetic distances between individuals in three dimensions. Identity by state distances in Northern Europe (left), and Sweden and Finland (right). The proportions of variance explained by the three axes are 0.64%, 0.24%, and 0.17% in Northern Europe and 1.04%, 0.26%, and 0.24% in Sweden and Finland, respectively. The animation files can be opened e.g. in most internet browsers. Abbreviations as in Table 1 and Table S1. (GIF)
    Full-text Dataset · Feb 2011
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    Dataset: Figure S3
    Elina Salmela · Tuuli Lappalainen · Jianjun Liu · [...] · Juha Kere
    [Show abstract] [Hide abstract] ABSTRACT: FST distances visualized by multidimensional scaling. Pairwise distances between European populations (a), Swedish and Finnish provinces (b), and Swedish provinces (c). The corresponding FST values can be found in Tables S2-S4. Abbreviations: Toscans in Italy (TSI) from HapMap; French (FRE), French Basque (FRB), North Italian (ITN), Orcadian (ORC), and Sardinian (SAR) from HGDP; Swedes with geographical information (NORR+SVEA+GOTA) (SWE); other abbreviations as in Table 1 and Table S1. (TIF)
    Full-text Dataset · Feb 2011
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    Dataset: Table S1
    Elina Salmela · Tuuli Lappalainen · Jianjun Liu · [...] · Juha Kere
    [Show abstract] [Hide abstract] ABSTRACT: Names, abbreviations and sample sizes for the Swedish and Finnish provinces. (XLS)
    Full-text Dataset · Feb 2011
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    Dataset: Figure S2
    Elina Salmela · Tuuli Lappalainen · Jianjun Liu · [...] · Juha Kere
    [Show abstract] [Hide abstract] ABSTRACT: The probabilities of different numbers of clusters (K) in the Structure analysis of Northern Europe. (TIF)
    Full-text Dataset · Feb 2011
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    Dataset: Figure S10
    Elina Salmela · Tuuli Lappalainen · Jianjun Liu · [...] · Juha Kere
    [Show abstract] [Hide abstract] ABSTRACT: Differences between cases and controls in Dataset 3. A quantile-quantile plot of observed vs. expected test statistics (in blue) from a chi-square test of allele frequency differences between cases and controls for the SNPs that remain in Dataset 3 after quality control. Lambda denotes the overdispersion factor of observed vs. expected chi-square statistics. (TIF)
    Full-text Dataset · Feb 2011
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    Dataset: Table S4
    Elina Salmela · Tuuli Lappalainen · Jianjun Liu · [...] · Juha Kere
    [Show abstract] [Hide abstract] ABSTRACT: Pairwise FST values (multiplied by 10,000) between Swedish provinces. (XLS)
    Full-text Dataset · Feb 2011