| 51. |
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| 52. |
- Maruani, Anna, et al.
(author)
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11q24.2-25 micro-rearrangements in autism spectrum disorders: Relation to brain structures
- 2015
-
In: American Journal of Medical Genetics. Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 167:12, s. 3019-3030
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Journal article (peer-reviewed)abstract
- Jacobsen syndrome (JS) is characterized by intellectual disability and higher risk for autism spectrum disorders (ASD). All patients with JS are carriers of contiguous de novo deletions of 11q24.2-25, but the causative genes remain unknown. Within the critical interval, we hypothesized that haploinsufficiency of the neuronal cell adhesion molecule Neurotrimin (NTM) might increase the risk for ASD and could affect brain structure volumes. We searched for deleterious mutations affecting NTM in 1256 ASD patients and 1287 controls, using SNP arrays, and by direct sequencing of 250 ASD patients and 180 controls. We compared our results to those obtained from independent cohorts of ASD patients and controls. We identified two patients with Copy Number Variants (CNV) encompassing NTM, one with a large de novo deletion, and a clinical phenotype of JS (including macrocephaly), and a second with a paternally inherited duplication, not consistent with JS. Interestingly, no similar CNVs were observed in controls. We did not observe enrichment for deleterious NTM mutations in our cohort. We then explored if the macrocephaly in the patient with JS was associated with a homogeneous increase of brain structures volumes using automatic segmentation. Compared to subjects without NTM micro-rearrangements (n=188), the patient had an increased volume of the sub-cortical structures but a decrease of the occipital gray matter. Finally our explorations could not incriminate NTM as a susceptibility gene for ASD, but provides new information on the impact of the 11q24.2-25 deletion on brain anatomy. © 2015 Wiley Periodicals, Inc.
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| 53. |
- Melke, Jonas, 1971, et al.
(author)
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Abnormal melatonin synthesis in autism spectrum disorders.
- 2008
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In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 13:1, s. 90-98
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Journal article (peer-reviewed)abstract
- Melatonin is produced in the dark by the pineal gland and is a key regulator of circadian and seasonal rhythms. A low melatonin level has been reported in individuals with autism spectrum disorders (ASD), but the underlying cause of this deficit was unknown. The ASMT gene, encoding the last enzyme of melatonin synthesis, is located on the pseudo-autosomal region 1 of the sex chromosomes, deleted in several individuals with ASD. In this study, we sequenced all ASMT exons and promoters in individuals with ASD (n=250) and compared the allelic frequencies with controls (n=255). Non-conservative variations of ASMT were identified, including a splicing mutation present in two families with ASD, but not in controls. Two polymorphisms located in the promoter (rs4446909 and rs5989681) were more frequent in ASD compared to controls (P=0.0006) and were associated with a dramatic decrease in ASMT transcripts in blood cell lines (P=2 x 10(-10)). Biochemical analyses performed on blood platelets and/or cultured cells revealed a highly significant decrease in ASMT activity (P=2 x 10(-12)) and melatonin level (P=3 x 10(-11)) in individuals with ASD. These results indicate that a low melatonin level, caused by a primary deficit in ASMT activity, is a risk factor for ASD. They also support ASMT as a susceptibility gene for ASD and highlight the crucial role of melatonin in human cognition and behavior.
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| 54. |
- Mullins, Niamh, et al.
(author)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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In: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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| 55. |
- Mullins, Niamh, et al.
(author)
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GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores
- 2019
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In: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 176:8, s. 651-660
-
Journal article (peer-reviewed)abstract
- Objective: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.Methods: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.Results: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).Conclusions: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.
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| 56. |
- Nava, C, et al.
(author)
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Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE.
- 2012
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In: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 2
-
Journal article (peer-reviewed)abstract
- The striking excess of affected males in autism spectrum disorders (ASD) suggests that genes located on chromosome X contribute to the etiology of these disorders. To identify new X-linked genes associated with ASD, we analyzed the entire chromosome X exome by next-generation sequencing in 12 unrelated families with two affected males. Thirty-six possibly deleterious variants in 33 candidate genes were found, including PHF8 and HUWE1, previously implicated in intellectual disability (ID). A nonsense mutation in TMLHE, which encodes the ɛ-N-trimethyllysine hydroxylase catalyzing the first step of carnitine biosynthesis, was identified in two brothers with autism and ID. By screening the TMLHE coding sequence in 501 male patients with ASD, we identified two additional missense substitutions not found in controls and not reported in databases. Functional analyses confirmed that the mutations were associated with a loss-of-function and led to an increase in trimethyllysine, the precursor of carnitine biosynthesis, in the plasma of patients. This study supports the hypothesis that rare variants on the X chromosome are involved in the etiology of ASD and contribute to the sex-ratio disequilibrium.
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| 57. |
- Ou, Anna H., et al.
(author)
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Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study
- 2024
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In: TRANSLATIONAL PSYCHIATRY. - 2158-3188. ; 14:1
-
Journal article (peer-reviewed)abstract
- Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.
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| 58. |
- Philippe, Anne, et al.
(author)
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Analysis of ten candidate genes in autism by association and linkage
- 2002
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In: American Journal of Medical Genetics. - : Wiley. - 0148-7299. ; 114:2, s. 125-128
-
Journal article (peer-reviewed)abstract
- We studied the possible involvement of ten candidate genes in autism: proenkephalin, prodynorphin, and proprotein convertase subtilisin/kexin type 2 (opioid metabolism); tyrosine hydroxylase, dopamine receptors D2 and D5, monoamine oxidases A and B (monoaminergic system); brain-derived neurotrophic factor, and neural cell adhesion molecule (involved in neurodevelopment). Thirty-eight families with two affected siblings and one family with two affected half-siblings, recruited by the Paris Autism Research International Sibpair Study (PARIS), were tested using the transmission disequilibrium test and two-point affected sib-pair linkage analysis. We found no evidence for association or linkage with intragenic or linked markers. Our family sample has good power for detecting a linkage disequilibrium of 0.80. Thus, these genes are unlikely to play a major role in the families studied, but further studies in a much larger sample would be needed to highlight weaker genetic effects.
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| 59. |
- Philippe, Anne, et al.
(author)
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Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study.
- 1999
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 8:5, s. 805-812
-
Journal article (peer-reviewed)abstract
- Family and twin studies have suggested a genetic component in autism. We performed a genome-wide screen with 264 microsatellites markers in 51 multiplex families, using non-parametric linkage methods. Families were recruited by a collaborative group including clinicians from Sweden, France, Norway, the USA, Italy, Austria and Belgium. Using two-point and multipoint affected sib-pair analyses, 11 regions gave nominal P-values of 0.05 or lower. Four of these regions overlapped with regions on chromosomes 2q, 7q, 16p and 19p identified by the first genome-wide scan of autism performed by the International Molecular Genetic Study of Autism Consortium. Another of our potential susceptibility regions overlapped with the 15q11–q13 region identified in previous candidate gene studies. Our study revealed six additional regions on chromosomes 4q, 5p, 6q, 10q, 18q and Xp. We found that the most significant multipoint linkage was close to marker D6S283 (maximum lod score = 2.23, P= 0.0013)
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| 60. |
- Sato, Daisuke, et al.
(author)
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SHANK1 Deletions in Males with Autism Spectrum Disorder.
- 2012
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 90:5, s. 879-887
-
Journal article (peer-reviewed)abstract
- Recent studies have highlighted the involvement of rare (<1% frequency) copy-number variations and point mutations in the genetic etiology of autism spectrum disorder (ASD); these variants particularly affect genes involved in the neuronal synaptic complex. The SHANK gene family consists of three members (SHANK1, SHANK2, and SHANK3), which encode scaffolding proteins required for the proper formation and function of neuronal synapses. Although SHANK2 and SHANK3 mutations have been implicated in ASD and intellectual disability, the involvement of SHANK1 is unknown. Here, we assess microarray data from 1,158 Canadian and 456 European individuals with ASD to discover microdeletions at the SHANK1 locus on chromosome 19. We identify a hemizygous SHANK1 deletion that segregates in a four-generation family in which male carriers-but not female carriers-have ASD with higher functioning. A de novo SHANK1 deletion was also detected in an unrelated male individual with ASD with higher functioning, and no equivalent SHANK1 mutations were found in >15,000 controls (p = 0.009). The discovery of apparent reduced penetrance of ASD in females bearing inherited autosomal SHANK1 deletions provides a possible contributory model for the male gender bias in autism. The data are also informative for clinical-genetics interpretations of both inherited and sporadic forms of ASD involving SHANK1.
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