Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.</p

Ancient human genomes suggest three ancestral populations for present-day Europeans

We sequenced the genomes of a 7,000-year-old farmer from Germany and eight 8,000-year-old hunter-gatherers from Luxembourg and Sweden. We analysed these and other ancient genomes¹-₄ with 2,345 contemporary humans to show that most present-day Europeans derive from at least three highly differentiated populations:west European hunter-gatherers, who contributed ancestry to all Europeans but not to Near Easterners; ancient north Eurasians related to Upper Palaeolithic Siberians³, who contributed to both Europeans and Near Easterners; and early European farmers, who were mainly of Near Eastern origin but also harboured west European hunter-gatherer related ancestry.We model these populations’ deep relationships and show that early European farmers had 44% ancestry from a ‘basal Eurasian’ population that split before the diversification of other non-African lineage

Biological insights from 108 schizophrenia-associated genetic loci

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10-4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10-7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies

Genomic Evidence Suggests Further Changes of Butterfly Names

Further genomic sequencing of butterflies by our research group expanding the coverage of species and specimens from different localities, coupled with genome-scale phylogenetic analysis and complemented by phenotypic considerations, suggests a number of changes to the names of butterflies, mostly those recorded from the United States and Canada. Here, we present evidence to support these changes. The changes are intended to make butterfly classification more internally consistent at the genus, subgenus and species levels. That is, considering all available evidence, we attempt to assign similar taxonomic ranks to the clades of comparable genetic differentiation, which on average is correlated with the age of phylogenetic groups estimated from trees. For species, we use criteria devised by genomic analysis of the genetic differentiation across suture zones and comparison of sympatric populations of closely related species. As a result, we resurrect 4 genera and 1 subgenus from subgeneric status or synonymy, change the rank of 8 currently used genera to subgenus, synonymize 7 genus-group names, summarize evidence to support 19 taxa as species instead of subspecies and 1 taxon as subspecies instead of species, along with a number of additional changes. One new genus and one new subspecies are described. Namely, the following taxa are treated as genera Tharsalea Scudder, 1876, Helleia Verity, 1943, Apangea Zhdanko, 1995, and Boldenaria Zhdanko, 1995. Tetracharis Grote, 1898 is a valid subgenus (not a synonym of Anthocharis Boisduval, Rambur, [Duménil] & Graslin, [1833]) that consists of Anthocharis cethura C. Felder & R. Felder, 1865 (Müller, 1764), Anthocharis midea (Hübner, [1809]), and Anthocharis limonea (A. Butler, 1871). The following are subgenera: Speyeria Scudder, 1872 of Argynnis Fabricius, 1807; Aglais Dalman, 1816 and Polygonia Hübner, [1819] of Nymphalis Kluk, 1780; Palaeonympha Butler, 1871 of Megisto Hübner, [1819]; Hyponephele Muschamp, 1915 of Cercyonis Scudder, 1875; Pyronia Hübner, [1819] and Aphantopus Wallengren, 1853 of Maniola Schrank, 1801 and Pseudonymphidia Callaghan, 1985 of Pachythone. Lafron Grishin, gen. n. (type species Papilio orus Stoll, [1780], parent subfamily Lycaeninae [Leach], [1815]) is described. Dipsas japonica Murray, 1875 is fixed as the type species of Neozephyrus Sibatani & Ito, 1942. The following taxa are junior subjective synonyms: Falcapica Klots, 1930 of Tetracharis Grote, 1898; Habrodais Scudder, 1876, Favonius Sibatani & Ito, 1942, Neozephyrus Sibatani & Ito, 1942, Quercusia Verity, 1943, Chrysozephyrus Shirôzu & Yamamoto, 1956, and Sibataniozephyrus Inomata, 1986 of Hypaurotis Scudder, 1876; Plesioarida Trujano & García, 2018 of Roeberella Strand, 1932; Papilio temenes Godart, 1819 (lectotype designated herein) of Heraclides aristodemus (Esper, 1794), Speyeria hydaspe conquista dos Passos & Grey, 1945 of Argynnis hesperis tetonia (dos Passos & Grey, 1945), and Erycides imbreus Plötz, 1879 of Phocides polybius polybius (Fabricius, 1793). The following are revised genus-species combinations: Pachythone lencates (Hewitson, 1875) Pachythone flocculus (Brévignon & Gallard, 1993), Pachythone floccus (Brévignon, 2013), Pachythone heberti (P. Jauffret & J. Jauffret, 2007), Pachythone marajoara (P. Jauffret & J. Jauffret, 2007) and Cissia cleophes (Godman & Salvin, 1889). The following species are transferred between subgenera: Anthocharis lanceolata Lucas, 1852 belongs to Anthocharis Boisduval, Rambur, [Duménil] & Graslin, [1833] instead of Paramidea Kuznetsov, 1929 and Danaus eresimus (Cramer, 1777) belongs to Danaus Kluk, 1780, and not to Anosia Hübner, 1816. The following taxa are distinct species rather than subspecies (of species shown in parenthesis): Heraclides ponceana (Schaus, 1911) (not Heraclides aristodemus (Esper, 1794)), Colias elis Strecker, 1885 (not Colias meadii W. H. Edwards, 1871), Argynnis irene Boisduval, 1869 and Argynnis nausicaa W. H. Edwards, 1874 (not Argynnis hesperis W. H. Edwards, 1864), Coenonympha california Westwood, [1851] (not Coenonympha tullia (Müller, 1764)), Dione incarnata N. Riley, 1926 (not Dione vanillae (Linnaeus, 1758)), Chlosyne coronado (M. Smith & Brock, 1988) (not Chlosyne fulvia (W. H. Edwards, 1879)), Chlosyne chinatiensis (Tinkham, 1944) (not Chlosyne theona (Ménétriés, 1855)), Phocides lilea (Reakirt, [1867]) (not Phocides polybius (Fabricius, 1793)), Cecropterus nevada (Scudder, 1872) and Cecropterus dobra (Evans, 1952) (not Cecropterus mexicana (Herrich-Schäffer, 1869)), Telegonus anausis Godman & Salvin, 1896, (not Telegonus anaphus (Cramer, 1777)), Epargyreus huachuca Dixon, 1955 (not Epargyreus clarus (Cramer, 1775)), Nisoniades bromias (Godman & Salvin, 1894) (not Nisoniades rubescens (Möschler, 1877)), Pholisora crestar J. Scott & Davenport, 2017 (not Pholisora catullus (Fabricius, 1793)), Carterocephalus mandan (W. H. Edwards, 1863) and Carterocephalus skada (W. H. Edwards, 1870) (not Carterocephalus palaemon (Pallas, 1771)), Amblyscirtes arizonae H. Freeman, 1993 (not Amblyscirtes elissa Godman, 1900), and Megathymus violae D. Stallings & Turner, 1956 (not Megathymus ursus Poling, 1902). Resulting from these changes, the following are revised species-subspecies combinations: Heraclides ponceana bjorndalae (Clench, 1979), Heraclides ponceana majasi L. Miller, 1987, Argynnis irene dodgei Gunder, 1931, Argynnis irene cottlei J. A. Comstock, 1925, Argynnis irene hanseni (J. Emmel, T. Emmel & Mattoon, 1998), Argynnis nausicaa elko (Austin, 1984), Argynnis nausicaa greyi (Moeck, 1950), Argynnis nausicaa viola (dos Passos & Grey, 1945), Argynnis nausicaa tetonia (dos Passos & Grey, 1945), Argynnis nausicaa chitone W. H. Edwards, 1879, Argynnis nausicaa schellbachi (Garth, 1949), Argynnis nausicaa electa W. H. Edwards, 1878, Argynnis nausicaa dorothea (Moeck, 1947), and Argynnis nausicaa capitanensis (R. Holland, 1988), Argynnis zerene atossa W. H. Edwards, 1890, Dione incarnata nigrior (Michener, 1942), Chlosyne coronado pariaensis (M. Smith & Brock, 1988), Cecropterus nevada aemilea (Skinner, 1893), Cecropterus nevada blanca (J. Scott, 1981), Telegonus anausis annetta (Evans, 1952), Telegonus anausis anoma (Evans, 1952), Telegonus anausis aniza (Evans, 1952), Epargyreus huachuca profugus Austin, 1998, Carterocephalus mandan mesapano (Scudder, 1868) and Carterocephalus skada magnus Mattoon & Tilden, 1998. American Coenonympha subspecies placed under C. tullia other than Coenonympha tullia kodiak W. H. Edwards, 1869, Coenonympha tullia mixturata Alpheraky, 1897 and Coenonympha tullia yukonensis W. Holland, 1900 belong to C. california. Heraclides ponceana latefasciatus Grishin, ssp. n. is described from Cuba. Argynnis coronis carolae dos Passos & Grey, 1942 is considered a subspecies-level taxon. Unless stated otherwise, all subgenera, species, subspecies and synonyms of mentioned genera and species are transferred together with their parent taxa, and others remain as previously classified

Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study

BACKGROUND: C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal. METHODS AND FINDINGS: We performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRSCRP), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRSGWAS). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed. The strengths (F-statistics) of the IVs were 31.92-3,761.29 and 82.32-9,403.21 for GRSCRP and GRSGWAS, respectively. CRP GRSGWAS showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79-0.94]; p < 0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94-0.98]; p < 1.72 × 10-6). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 × 10-4, 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRPPRS (built of SNPs with p < 1 × 10-4) showed a statistically significant (p < 2.45 × 10-4) protective effect with an OR of 0.97 (95% CI 0.95-0.99). The CRP GRSGWAS showed that a 10% increase in genetically determined CRP level was significantly associated with coronary artery disease (OR 0.88 [95% CI 0.84-0.94]; p < 2.4 × 10-5) and was nominally associated with the risk of inflammatory bowel disease (OR 0.85 [95% CI 0.74-0.98]; p < 0.03), Crohn disease (OR 0.81 [95% CI 0.70-0.94]; p < 0.005), psoriatic arthritis (OR 1.36 [95% CI 1.00-1.84]; p < 0.049), knee osteoarthritis (OR 1.17 [95% CI 1.01-1.36]; p < 0.04), and bipolar disorder (OR 1.21 [95% CI 1.05-1.40]; p < 0.007) and with an increase of 0.72 (95% CI 0.11-1.34; p < 0.02) mm Hg in systolic blood pressure, 0.45 (95% CI 0.06-0.84; p < 0.02) mm Hg in diastolic blood pressure, 0.01 ml/min/1.73 m2 (95% CI 0.003-0.02; p < 0.005) in estimated glomerular filtration rate from serum creatinine, 0.01 g/dl (95% CI 0.0004-0.02; p < 0.04) in serum albumin level, and 0.03 g/dl (95% CI 0.008-0.05; p < 0.009) in serum protein level. However, after adjustment for heterogeneity, neither GRS showed a significant effect of CRP level (at p < 0.0016) on any of these outcomes, including coronary artery disease, nor on the other 20 complex outcomes studied. Our study has two potential limitations: the limited variance explained by our genetic instruments modeling CRP levels in blood and the unobserved bias introduced by the use of summary statistics in our MR analyses. CONCLUSIONS: Genetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia. We observed nominal evidence at an observed p < 0.05 using either GRSCRP or GRSGWAS-with persistence after correction for heterogeneity-for a causal relationship of elevated CRP levels with psoriatic osteoarthritis, rheumatoid arthritis, knee osteoarthritis, systolic blood pressure, diastolic blood pressure, serum albumin, and bipolar disorder. These associations remain yet to be confirmed. We cannot verify any causal effect of CRP level on any of the other common somatic and neuropsychiatric outcomes investigated in the present study. This implies that interventions that lower CRP level are unlikely to result in decreased risk for the majority of common complex outcomes

The Simons Genome Diversity Project : 300 genomes from 142 diverse populations.

Here we report the Simons Genome Diversity Project data set: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioural modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that of other non-Africans.Facultad de Ciencias Naturales y Muse