| 1. |
- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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| 2. |
- Turcot, Valerie, et al.
(författare)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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| 3. |
- Savage, J. E., et al.
(författare)
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Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:7, s. 912-919
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Tidskriftsartikel (refereegranskat)abstract
- Intelligence is highly heritable 1 and a major determinant of human health and well-being 2 . Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence 3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
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| 4. |
- Tielbeek, J. J., et al.
(författare)
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Genome-Wide Association Studies of a Broad Spectrum of Antisocial Behavior
- 2017
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Ingår i: Jama Psychiatry. - : American Medical Association (AMA). - 2168-622X .- 2168-6238. ; 74:12, s. 1242-1250
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic variants have, however, not been identified. OBJECTIVES To estimate the single-nucleotide polymorphism-based heritability of ASB; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to reevaluate the candidate gene era data through the Broad Antisocial Behavior Consortium. DESIGN, SETTING, AND PARTICIPANTS Genome-wide association data from 5 large population-based cohorts and 3 target samples with genome-wide genotype and ASB data were used for meta-analysis from March 1, 2014, to May 1, 2016. All data sets used quantitative phenotypes, except for the Finnish Crime Study, which applied a case-control design (370 patients and 5850 control individuals). MAIN OUTCOME AND MEASURES This study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derived from multiple measures, maximizing the sample size over different age ranges. RESULTS The discovery samples comprised 16 400 individuals, whereas the target samples consisted of 9381 individuals (all individuals were of European descent), including child and adult samples (mean age range, 6.7-56.1 years). Three promising loci with sex-discordant associations were found (8535 female individuals, chromosome 1: rs2764450, chromosome 11: rs11215217; 7772 male individuals, chromosome X, rs41456347). Polygenic risk score analyses showed prognostication of antisocial phenotypes in an independent Finnish Crime Study (2536 male individuals and 3684 female individuals) and shared genetic origin with conduct problems in a population-based sample (394 male individuals and 431 female individuals) but not with conduct disorder in a substance-dependent sample (950 male individuals and 1386 female individuals) (R-2 = 0.0017 in the most optimal model, P = 0.03). Significant inverse genetic correlation of ASB with educational attainment (r = -0.52, P =.005) was detected. CONCLUSIONS AND RELEVANCE The Broad Antisocial Behavior Consortium entails the largest collaboration to date on the genetic architecture of ASB, and the first results suggest that ASB may be highly polygenic and has potential heterogeneous genetic effects across sex.
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| 5. |
- Pettersson, E., et al.
(författare)
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Genetic influences on eight psychiatric disorders based on family data of 4 408 646 full and half-siblings, and genetic data of 333 748 cases and controls
- 2019
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Ingår i: Psychological Medicine. - : Cambridge University Press. - 0033-2917 .- 1469-8978. ; 49:7, s. 1166-1173
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Most studies underline the contribution of heritable factors for psychiatric disorders. However, heritability estimates depend on the population under study, diagnostic instruments, and study designs that each has its inherent assumptions, strengths, and biases. We aim to test the homogeneity in heritability estimates between two powerful, and state of the art study designs for eight psychiatric disorders.METHODS: We assessed heritability based on data of Swedish siblings (N = 4 408 646 full and maternal half-siblings), and based on summary data of eight samples with measured genotypes (N = 125 533 cases and 208 215 controls). All data were based on standard diagnostic criteria. Eight psychiatric disorders were studied: (1) alcohol dependence (AD), (2) anorexia nervosa, (3) attention deficit/hyperactivity disorder (ADHD), (4) autism spectrum disorder, (5) bipolar disorder, (6) major depressive disorder, (7) obsessive-compulsive disorder (OCD), and (8) schizophrenia.RESULTS: Heritability estimates from sibling data varied from 0.30 for Major Depression to 0.80 for ADHD. The estimates based on the measured genotypes were lower, ranging from 0.10 for AD to 0.28 for OCD, but were significant, and correlated positively (0.19) with national sibling-based estimates. When removing OCD from the data the correlation increased to 0.50.CONCLUSIONS: Given the unique character of each study design, the convergent findings for these eight psychiatric conditions suggest that heritability estimates are robust across different methods. The findings also highlight large differences in genetic and environmental influences between psychiatric disorders, providing future directions for etiological psychiatric research.
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| 6. |
- Van Eck, C.L., et al.
(författare)
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Polarized point sources in the LOFAR Two-meter Sky Survey: A preliminary catalog
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 613
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Forskningsöversikt (refereegranskat)abstract
- The polarization properties of radio sources at very low frequencies (<200 MHz) have not been widely measured, but the new generation of low-frequency radio telescopes, including the Low Frequency Array (LOFAR: a Square Kilometre Array Low pathfinder), now gives us the opportunity to investigate these properties. In this paper, we report on the preliminary development of a data reduction pipeline to carry out polarization processing and Faraday tomography for data from the LOFAR Two-meter Sky Survey (LOTSS) and present the results of this pipeline from the LOTSS preliminary data release region (10h45m–15h30m right ascension, 45°–57° declination, 570 square degrees). We have produced a catalog of 92 polarized radio sources at 150 MHz at 4.′3 resolution and 1 mJy rms sensitivity, which is the largest catalog of polarized sources at such low frequencies. We estimate a lower limit to the polarized source surface density at 150 MHz, with our resolution and sensitivity, of 1 source per 6.2 square degrees. We find that our Faraday depth measurements are in agreement with previous measurements and have significantly smaller errors. Most of our sources show significant depolarization compared to 1.4 GHz, but there is a small population of sources with low depolarization indicating that their polarized emission is highly localized in Faraday depth. We predict that an extension of this work to the full LOTSS data would detect at least 3400 polarized sources using the same methods, and probably considerably more with improved data processing.
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| 7. |
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| 8. |
- Polderman, T. J. C., et al.
(författare)
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The co-occurrence of autistic and ADHD dimensions in adults : an etiological study in 17,770 twins
- 2014
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Ingår i: Translational Psychiatry. - New York, USA : Nature Publishing Group. - 2158-3188. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) often occur together. To obtain more insight in potential causes for the co-occurrence, this study examined the genetic and environmental etiology of the association between specific ASD and ADHD disorder dimensions. Self-reported data on ASD dimensions social and communication difficulties (ASDsc), and repetitive and restricted behavior and interests (ASDr), and ADHD dimensions inattention (IA), and hyperactivity/impulsivity (HI) were assessed in a community sample of 17,770 adult Swedish twins. Phenotypic, genetic and environmental associations between disorder dimensions were examined in a multivariate model, accounting for sex differences. ASDr showed the strongest associations with IA and HI in both sexes (r(p) 0.33 to 0.40). ASDsc also correlated moderately with IA (females r(p) 0.29 and males r(p) 0.35) but only modestly with HI (females r(p) 0.17 and males r(p) 0.20). Genetic correlations ranged from 0.22 to 0.64 and were strongest between ASDr and IA and HI. Sex differences were virtually absent. The ASDr dimension (reflecting restricted, repetitive and stereotyped patterns of behavior, interests and activities) showed the strongest association with dimensions of ADHD, on a phenotypic, genetic and environmental level. This study opens new avenues for molecular genetic research. As our findings demonstrated that genetic overlap between disorders is dimension-specific, future gene-finding studies on psychiatric comorbidity should focus on carefully selected genetically related dimensions of disorders.
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