| 61. |
- Jonsson, Lina, 1982, et al.
(author)
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Association study between autistic-like traits and polymorphisms in the autism candidate regions RELN, CNTNAP2, SHANK3, and CDH9/10
- 2014
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In: Molecular Autism. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 2040-2392.
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Journal article (peer-reviewed)abstract
- Background: Autistic-like traits (ALTs) are continuously distributed in the general population, with the autism spectrum disorder (ASD) at the upper extreme end. A genetic overlap has been shown between ALTs and ASD, indicating that common variation in ASD candidate genes may also influence ALTs. In our study, we have investigated the SNP rs4307059 that has been associated with both ALTs and ASD. In addition, we genotyped polymorphisms in a selection of genes involved in synaptic functioning, that is, SHANK3, RELN, and CNTNAP2, which repeatedly have been associated with ASD. The possible associations of these polymorphisms with ALTs, as well as genetic factors for neurodevelopmental problems (NDPs), were investigated in a large cohort from the general population: The Child and Adolescent Twin Study in Sweden. For analyses of ALTs and NDPs, 12,319 subjects (including 2,268 monozygotic (MZ) and 3,805 dizygotic (DZ) twin pairs) and 8,671 subjects (including 2,243 MZ and 2,044 DZ twin pairs), respectively, were included in the analyses. Findings: We could not replicate the previous association between rs4307059 and social communication impairment. Moreover, common variations in CNTNAP2 (rs7794745 and rs2710102), RELN (rs362691), and SHANK3 (rs9616915) were not significantly associated with ALTs in our study. Conclusions: Our results do not suggest that the investigated genes, which previously has been found associated with ASD diagnosis, have any major influence on ALTs in children from the general population.
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| 62. |
- Jonsson, Lina, 1982, et al.
(author)
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Examining neurodevelopmental problems in 15q11.2 (BP1-BP2) copy number variation carriers at ages 9/12 and 18 in a Swedish twin sample
- 2023
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In: Molecular Genetics & Genomic Medicine. - 2324-9269. ; 11:8
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Journal article (peer-reviewed)abstract
- BackgroundSeveral copy number variations (CNVs) are associated with increased risk for neurodevelopmental and psychiatric disorders. The CNV 15q11.2 (BP1-BP2) deletion has been associated with learning difficulties, attention deficit hyperactivity disorder (ADHD), epilepsy, and brain morphology; however, many carriers present mild or no symptoms. Carrying the reciprocal duplication does not seem to confer risk for these disorders or traits. Our aim was to examine the impact of carrying either 15q11.2 deletion and reciprocal duplication on neurodevelopmental problems in a population-based sample of children. MethodsTwins with genotype and phenotype information in the Child and Adolescent Twin Study in Sweden (CATSS) were included (N = 12,040). We included measures of neurodevelopmental problems (NDPs), including learning problems, from the questionnaire Autism-Tics, ADHD, and other Comorbidities inventory (A-TAC) at age 9/12, ADHD and autism spectrum disorder (ASD) questionnaires at age 18, as well as information about lifetime psychiatric diagnoses and epileptic seizures. We tested the association between these phenotypic measurements and carrying the 15q11.2 deletion, the reciprocal duplication, and other CNVs with previously reported strong associations with neurodevelopmental and psychiatric disorders (i.e., psychiatric CNVs). ResultsWe identified 57 carriers of the 15q11.2 deletion, 75 carriers of the reciprocal duplication, and 67 carriers of other psychiatric CNVs. We did not find an increased risk for NDPs or psychiatric diagnoses in the 15q11.2 deletion carriers. For 15q11.2 duplication carriers, we found an increased risk for math learning problems and fewer self-reported ADHD symptoms at age 18 but not for other NDPs. In line with previous studies, we found an increased risk of NDPs and other evaluated phenotypes in carriers of psychiatric CNVs. ConclusionsOur results support previous findings that carrying 15q11.2 deletion does not have a large effect on NDPs in children.
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| 63. |
- Jönsson, Erik G, et al.
(author)
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Monoamine related functional gene variants and relationships to monoamine metabolite concentrations in CSF of healthy volunteers.
- 2004
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In: BMC psychiatry. - 1471-244X. ; 4
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Journal article (peer-reviewed)abstract
- BACKGROUND: Concentrations of monoamine metabolites in human cerebrospinal fluid (CSF) have been used extensively as indirect estimates of monoamine turnover in the brain. CSF monoamine metabolite concentrations are partly determined by genetic influences. METHODS: We investigated possible relationships between DNA polymorphisms in the serotonin 2C receptor (HTR2C), the serotonin 3A receptor (HTR3A), the dopamine D4 receptor (DRD4), and the dopamine beta-hydroxylase (DBH) genes and CSF concentrations of 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 90). RESULTS: The HTR3A 178 C/T variant was associated with 5-HIAA levels (p = 0.02). The DBH-1021 heterozygote genotype was associated with 5-HIAA (p = 0.0005) and HVA (p = 0.009) concentrations. Neither the HTR2C Cys23Ser variant, nor the DRD4 -521 C/T variant were significantly associated with any of the monoamine metabolites. CONCLUSIONS: The present results suggest that the HTR3A and DBH genes may participate in the regulation of dopamine and serotonin turnover rates in the central nervous system.
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| 64. |
- Karlsson, Sara, 1980, et al.
(author)
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Effects of sex and gonadectomy on social investigation and social recognition in mice
- 2015
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In: Bmc Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 16
-
Journal article (peer-reviewed)abstract
- Background: An individual's ability to recognise and pay attention to others is crucial in order to behave appropriately in various social situations. Studies in humans have shown a sex bias in sociability as well as social memory, indicating that females have better face memory and gaze more at the eyes of others, but information about the factors that underpin these differences is sparse. Our aim was therefore to investigate if sociability and social recognition differ between female and male mice, and if so, to what extent gonadal hormones may be involved. Intact and gona-dectomised male and female mice were assessed for sociability and social recognition using the three-chambered sociability paradigm, as well as the social discrimination test. Furthermore, we conducted a novel object recognition test, a locomotor activity test and an odour habituation/dishabituation test. Results: The present study showed that the ability to recognise other individuals is intact in males with and without gonads, as well as in intact females, whereas it is hampered in gonadectomised females. Additionally, intact male mice displayed more persistent investigatory behaviour compared to the other groups, although the intact females showed elevated basal locomotor activity. In addition, all groups had intact object memory and habituated to odours. Conclusions: Our results suggest that intact male mice investigate conspecifics more than females do, and these differences seem to depend upon circulating hormones released from the testis. As these results seem to contrast what is known from human studies, they should be taken into consideration when using the three-chambered apparatus, and similar paradigms as animal models of social deficits in e.g. autism. Other behavioural tests, and animal models, may be more suitable for translational studies between patients and experimental animals.
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| 65. |
- Karlsson, Sara, 1980, et al.
(author)
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Neural Androgen Receptors Modulate Gene Expression and Social Recognition But Not Social Investigation
- 2016
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In: Frontiers in Behavioral Neuroscience. - : Frontiers Media SA. - 1662-5153. ; 10
-
Journal article (peer-reviewed)abstract
- The role of sex and androgen receptors (ARs) for social preference and social memory is rather unknown. In this study of mice we compared males, females and males lacking ARs specifically in the nervous system, ARNesDel, with respect to social preference, assessed with the three-chambered apparatus test, and social recognition, assessed with the social discrimination procedure. In the social discrimination test we also evaluated the tentative importance of the sex of the stimulus animal. Novel object recognition and olfaction were investigated to complement the results from the social tests. Gene expression analysis was performed to reveal molecules involved in the effects of sex and androgens on social behaviors. All three test groups showed social preference in the three-chambered apparatus test. In both social tests an AR independent sexual dimorphism was seen in the persistence of social investigation of female conspecifics, whereas the social interest toward male stimuli mice was similar in all groups. Male and female controls recognized conspecifics independent of their sex, whereas ARNesDel males recognized female but not male stimuli mice. Moreover, the non-social behaviors were not affected by AR deficiency. The gene expression analyses of hypothalamus and amygdala indicated that Oxtr, Cd38, Esrl, Cyp19a1, Ucn3, Crh. and Gtf2i were differentially expressed between the three groups. In conclusion, our results suggest that ARs are required for recognition of male but not female conspecifics, while being dispensable for social investigation toward both sexes. In addition, the AR seems to regulate genes related to oxytocin, estrogen and William's syndrome.
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| 66. |
- Karlsson, Sara, 1980, et al.
(author)
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Social memory associated with estrogen receptor polymorphisms in women
- 2016
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In: Social Cognitive & Affective Neuroscience. - : Oxford University Press (OUP). - 1749-5016 .- 1749-5024. ; 11:6, s. 877-883
-
Journal article (peer-reviewed)abstract
- The ability to recognize the identity of faces and voices is essential for social relationships. Although the heritability of social memory is high, knowledge about the contributing genes is sparse. Since sex differences and rodent studies support an influence of estrogens and androgens on social memory, polymorphisms in the estrogen and androgen receptor genes (ESR1, ESR2, AR) are candidates for this trait. Recognition of faces and vocal sounds, separately and combined, was investigated in 490 subjects, genotyped for 10 single nucleotide polymorphisms (SNPs) in ESR1, four in ESR2 and one in the AR. Four of the associations survived correction for multiple testing: women carrying rare alleles of the three ESR2 SNPs, rs928554, rs1271572 and rs1256030, in linkage disequilibrium with each other, displayed superior face recognition compared with non-carriers. Furthermore, the uncommon genotype of the ESR1 SNP rs2504063 was associated with better recognition of identity through vocal sounds, also specifically in women. This study demonstrates evidence for associations in women between face recognition and variation in ESR2, and recognition of identity through vocal sounds and variation in ESR1. These results suggest that estrogen receptors may regulate social memory function in humans, in line with what has previously been established in mice.
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| 67. |
- Lagergren, K., et al.
(author)
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Polymorphisms in Genes of Relevance for Oestrogen and Oxytocin Pathways and Risk of Barrett's Oesophagus and Oesophageal Adenocarcinoma: A Pooled Analysis from the BEACON Consortium
- 2015
-
In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:9
-
Journal article (peer-reviewed)abstract
- Background The strong male predominance in oesophageal adenocarcinoma (OAC) and Barrett's oesophagus (BO) continues to puzzle. Hormonal influence, e.g. oestrogen or oxytocin, might contribute. This genetic-epidemiological study pooled 14 studies from three continents, Australia, Europe, and North America. Polymorphisms in 3 key genes coding for the oestrogen pathway (receptor alpha (ESR1), receptor beta (ESR2), and aromatase (CYP19A1)), and 3 key genes of the oxytocin pathway (the oxytocin receptor (OXTR), oxytocin protein (OXT), and cyclic ADP ribose hydrolase glycoprotein (CD38)), were analysed using a gene-based approach, versatile gene-based test association study (VEGAS). Among 1508 OAC patients, 2383 BO patients, and 2170 controls, genetic variants within ESR1 were associated with BO in males (p = 0.0058) and an increased risk of OAC and BO combined in males (p = 0.0023). Genetic variants within OXTR were associated with an increased risk of BO in both sexes combined (p = 0.0035) and in males (p = 0.0012). We followed up these suggestive findings in a further smaller data set, but found no replication. There were no significant associations between the other 4 genes studied and risk of OAC, BO, separately on in combination, in males and females combined or in males only. Genetic variants in the oestrogen receptor alpha and the oxytocin receptor may be associated with an increased risk of BO or OAC, but replication in other large samples are needed.
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| 68. |
- Landin, Jenny, et al.
(author)
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Oxytocin Receptors Regulate Social Preference in Zebrafish.
- 2020
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
-
Journal article (peer-reviewed)abstract
- With a strong tendency to socialise, the zebrafish is a useful model to study social behaviour, with implications for better treatments of social impairments, for instance in autism spectrum disorders. Although oxytocin is crucial for social behaviour in mammals, the importance of the fish orthologue - isotocin or zebrafish oxytocin (zOT) - for social behaviour in zebrafish is unclear. The aims of this study were firstly, to elucidate the receptor specificity of zOT and the related vasotocin or zebrafish vasopressin (zVP; the orthologue of mammalian vasopressin) and the nonpeptidergic oxytocin receptor antagonist L-368,899, and secondly to investigate if L-368,899 inhibits social preference in zebrafish. The potencies of ligands were evaluated for zOT/zVP family receptors in HEK293 cells. Adult and larval zebrafish were treated with L-368,899 or vehicle and subsequently assessed for social behaviour and anxiety (adults only). The antagonist L-368,899 specifically inhibited the two zOT receptors, but not the two zVP-1 receptors. The antagonist decreased social preference in adult and larval zebrafish. It did not affect anxiety in adults. These results indicate that endogenous zOT, and possibly zVP, is involved in social behaviour in zebrafish via either or both of the two zOT receptors, and show promise for future explorations of the anatomy and evolution of networks underlying social behaviour.
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| 69. |
- LoParo, D., et al.
(author)
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Rigorous Tests of Gene-Environment Interactions in a Lab Study of the Oxytocin Receptor Gene (OXTR), Alcohol Exposure, and Aggression
- 2016
-
In: American Journal of Medical Genetics Part B-Neuropsychiatric Genetics. - : Wiley. - 1552-4841. ; 171:5, s. 589-602
-
Journal article (peer-reviewed)abstract
- Naturalistic studies of gene-environment interactions (G X E) have been plagued by several limitations, including difficulty isolating specific environmental risk factors from other correlated aspects of the environment, gene-environment correlation (r(GE)), and the use of a single genetic variant to represent the influence of a gene. We present results from 235 Finnish young men in two lab studies of aggression and alcohol challenge that attempt to redress these limitations of the extant G X E literature. Specifically, we use a latent variable modeling approach in an attempt to more fully account for genetic variation across the oxytocin receptor gene (OXTR) and to robustly test its main effects on aggression and its interaction with alcohol exposure. We also modeled aggression as a latent variable comprising various indices, including the average and maximum levels of aggression, the earliest trial on which aggression was expressed, and the proportion of trials on which the minimum and maximum levels of aggression were expressed. The best fitting model for the genetic variation across OXTR included six factors derived from an exploratory factor analysis, roughly corresponding to six haplotype blocks. Aggression levels were higher on trials in which participants were administered alcohol, won, or were provoked. There was a significant main effect of OXTR on aggression across studies after controlling for covariates. The interaction of OXTR and alcohol was also significant across studies, such that OXTR had stronger effects on aggression in the alcohol administration condition. (C) 2015 Wiley Periodicals, Inc.
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| 70. |
- Martin, E M, et al.
(author)
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Molecular and neuroanatomical characterization of single neurons in the mouse medullary gigantocellular reticular nucleus.
- 2011
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In: The Journal of comparative neurology. - : Wiley. - 1096-9861 .- 0021-9967. ; 519:13, s. 2574-93
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Journal article (peer-reviewed)abstract
- Medullary gigantocellular reticular nucleus (mGi) neurons have been ascribed a variety of behaviors, many of which may fall under the concepts of either arousal or motivation. Despite this, many details of the connectivity of mGi neurons, particularly in reference to those neurons with ascending axons, remain unknown. To provide a neuroanatomical and molecular characterization of these cells, with reference to arousal and level-setting systems, large medullary reticular neurons were characterized with retrograde dye techniques and with real-time reverse transcriptase PCR (RT-PCR) analyses of single-neuron mRNA expression in the mouse. We have shown that receptors consistent with participation in generalized arousal are expressed by single mGi neurons and that receptors from different families of arousal-related neurotransmitters are rarely coexpressed. Through retrograde labeling, we have shown that neurons with ascending axons and neurons with descending axons tend to form like-with-like clusters, a finding that is consistent across age and gender. In comparing the two groups of retrogradely labeled neurons in neonatal animals, those neurons with axons that ascend to the midbrain show markers for GABAergic or coincident GABAergic and glutamatergic function; in contrast, approximately 60% of the neurons with axons that descend to the spinal cord are glutamatergic. We discuss the mGi's relationship to the voluntary and emotional motor systems and speculate that neurons in the mGi may represent a mammalian analogue to Mauthner cells, with a separation of function for neurons with ascending and descending axons.
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