| 1. |
- Anney, Richard, et al.
(författare)
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A genome-wide scan for common alleles affecting risk for autism.
- 2010
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:20, s. 4072-4082
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Tidskriftsartikel (refereegranskat)abstract
- Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
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| 2. |
- Pinto, Dalila, et al.
(författare)
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Functional impact of global rare copy number variation in autism spectrum disorders.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7304, s. 368-372
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Tidskriftsartikel (refereegranskat)abstract
- The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
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| 3. |
- Anney, Richard, et al.
(författare)
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Individual common variants exert weak effects on the risk for autism spectrum disorders.
- 2012
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:21, s. 4781-92
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Tidskriftsartikel (refereegranskat)abstract
- While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASD), the contribution of common variation to ASD risk is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating association of individual SNPs, we also sought evidence that common variants, en masse, might affect risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest p-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. By contrast, allele-scores derived from the transmission of common alleles to Stage 1 cases significantly predict case-status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele-score results, it is reasonable to conclude that common variants affect ASD risk but their individual effects are modest.
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| 4. |
- Casey, Jillian P, et al.
(författare)
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A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
- 2012
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 131:4, s. 565-579
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Tidskriftsartikel (refereegranskat)abstract
- Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
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| 5. |
- Szatmari, Peter, et al.
(författare)
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Mapping autism risk loci using genetic linkage and chromosomal rearrangements.
- 2007
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 39:3, s. 319-328
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Tidskriftsartikel (refereegranskat)abstract
- Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,168 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
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| 6. |
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| 7. |
- Hau, Stephan, 1960-, et al.
(författare)
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Interviewing women and couples after prenatal and genetic diagnostics
- 2008. - 1
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Ingår i: The Janus Face of Prenatal Diagnostics. - London : Karnac. - 9781855756748 - 1855756749 ; , s. 151-218
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Coping with modern technology (genetics, biotechnology etc.) has become a major issue of people living in the 21st century. This technology creates new chances and possibilities but also new dangers and ethical concerns. This book investigates ethical dilemmas connected to these new technologies in a field of prenatal and genetic research that seems particularly challenging: prenatal diagnostics. In the last decades enormous progress has been made in diagnosing genetically based diseases and other serious prenatal abnormalities. Despite intensive world-wide research, several problems have emerged and still wait to be answered. The most prominent aim of the book is to address major ethical dilemmas in the context of genetic and prenatal diagnosis, and by that means help to create greater awareness of and sensitivity to these dilemmas among various segments of the societies.
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| 8. |
- Levidioti-Lekkou, Spyridoula, 1945-
(författare)
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Adolescents' voices : mental health, self-esteem, sense of coherence, family functioning and life attitudes in Swedish and Greek adolescents
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Several factors have been identified as related to mental health in adolescence, such as competences, behavioural/emotional problems, self-esteem, and sense of coherence. Studies also emphasise the importance of family functioning and cultural factors.Objectives: This study investigates and compares the mental health of adolescents in relation to family functioning and socio-cultural variables in Sweden and Greece. Furthermore, Swedish and Greek adolescents' attitudes about life issues are studied. For Greek youths, mental health and gender variations in attitudes were studied as well.Populations and Methods: The study included 583 Swedish and 238 Greek school-aged adolescents aged 13 through 18 years. The Swedish sample was recruited from students at a Junior High and a High School in the town of Lycksele close to the University town of Umeå and the Greek sample was selected from three High schools and three Lyceums in Patras. The two samples were selected to represent the socio-demographic strata in the study areas.Achenbach's Youth Self Report (YSR), Rosenberg's Self-Esteem, Antonovsky's Sense of Coherence (SOC), and Beavers (SFI) scales were used. Out of the large sample, adolescents who reported either high or low on Achenbach's Youth Self Report–47 Greeks and 47 Swedes–were selected for semi-structured interviews.An interview guide with semi-structured questions was created to gather information about life attitudes. The questions addressed a broad spectrum of everyday life issues to understand how youths orient themselves to life–the central themes of an adolescent life and the basic codes of behaviour related to mental health, family, and culture.Results and discussion: Results revealed significant differences and some simi-larities between Swedish and Greek adolescents. According to YSR, the Swedish adolescents had fewer mental health problems than the Greek adolescents. Although this difference was most evident for internalized problems, it was also evident for externalized problems. These differences were seen for both sexes in most problem areas identified by YSR. In both countries, girls had higher prob-lem scores than boys. Age group comparisons followed the same national differences mostly obvious for the two oldest age groups. As for sense of coherence, all of the Greek groups had higher scores. For self-esteem, no differences were found in the comparison between total group scoring, but Greek girls and Swedish boys had better self-esteem compared to their counterparts. Greek adolescents scored their families higher on family health competence.With respect to attitudes about life issues, Greek youths reported more problems related to self, more fears of social dangers, losses, and illness. In addition, they turned more often to their family for support during difficult times. More Greek youths believed in God than their Swedish counterparts. The two groups identified similar family problems. The Swedes reported more fear about their future and tended to trust public authorities more during times of difficulty. Greek adolescents revealed social concerns, fears about the future and social dangers, and using own coping and family support to face these issues. Mental-health and gender patterns influenced some attitudes. Greek adolescents' attitudes about education, and messages sent to their parents are also presented. Both groups' attitudes about faith and homosexuality are shown.They both emphasised the importance of social and career position. Swedes, however, more often expressed a desire to have a family within five years. We recommend that counselling be offered in schools to provide students with life skills and to improve communication with their parents. This support should help parents and children face relational and behavioural issues of children. In addition, we recommend educational support be provided to Greek youths.
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