SHARED AND DISTINCT GENETIC INFLUENCES BETWEEN COGNITIVE DOMAINS AND PSYCHIATRIC DISORDER RISK BASED ON GENOME-WIDE DATA

AbstractDespite the strong genetic basis of psychiatric disorders, the molecular origins of these diseases are still largely unmapped. RNA-binding proteins (RBPs) are responsible for most post-transcriptional regulation, from splicing to translational to localization. RBPs thus act as key gatekeepers of cellular homeostasis, especially in the brain. Here, we leverage a deep learning approach to interrogate variant effects genome-wide, and discover that the dysregulation of RBP target sites is a principal contributor to psychiatric disorder risk. We show that specific modes of RBP regulation are genetically linked to the heritability of psychiatric disorders, and demonstrate that diverse RBP regulatory functions are reflected in distinct genome-wide negative selection signatures. Notably, RBP dysregulation has a stronger impact on psychiatric disorders than common coding region variants and explains heritability not currently captured by large-scale molecular QTL studies (expression QTLs and splicing QTLs). We share genome-wide profiles of RBP target site dysregulation, which we used to identify DDHD2 as a candidate schizophrenia risk gene, in a public web server. This resource provides a novel analytical framework to connect the full range of RNA regulation to complex disease.

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MEF2C Common Genetic Variation Is Associated With Different Aspects of Cognition in Non-Hispanic White and Caribbean Hispanic Non-demented Older Adults

Frontiers in Genetics ◽

10.3389/fgene.2021.642327 ◽

2021 ◽

Vol 12 ◽

Author(s):

Preeti Sunderaraman ◽

Stephanie Cosentino ◽

Nicole Schupf ◽

Jennifer Manly ◽

Yian Gu ◽

...

Keyword(s):

Older Adults ◽

Ethnic Groups ◽

Processing Speed ◽

Nucleotide Polymorphisms ◽

Association Analyses ◽

Cognitive Domains ◽

Genome Wide ◽

Genome Wide Data ◽

Washington Heights ◽

Hispanic White

ObjectivesMyocyte Enhancer Factor 2C (MEF2C) is identified as a candidate gene contributing to the risk of developing Alzheimer’s disease. However, little is known about whether MEF2C plays a role in specific aspects of cognition among older adults. The current study investigated the association of common variants in the MEF2C gene with four cognitive domains including memory, visuospatial functioning, processing speed and language among non-demented individuals.MethodParticipants from two ethnic groups, Non-Hispanic White (NHW; n = 537) and Caribbean Hispanic (CH; n = 1,197) from the Washington Heights-Inwood Community Aging Project (WHICAP) study, were included. Genetic association analyses using WHICAP imputed genome-wide data (GWAS) were conducted for the various cognition domains.ResultsSingle nucleotide polymorphisms (SNP) variants in the MEF2C gene showed nominally significant associations in all cognitive domains but for different SNPs across both the ethnic groups. In NHW participants, the strongest associations were present for memory (rs302484), language (rs619584), processing speed (rs13159808), and visuospatial functioning (several SNPs). In CH, strongest associations were observed for memory (rs34822815), processing speed (rs304141), visuospatial functioning (rs10066711 and rs10038371), and language (rs304153).DiscussionMEF2C variant-cognitive associations shed light on an apparent role for MEF2C in both memory and non-memory aspects of cognition in individuals from NHW and CH ancestries. However, the little overlap in the specific SNP-cognition associations in CH versus NHW highlights the differences in genetic architectural variations among those from different ancestries that should be considered while studying the MEF2C gene.

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Shared and distinct genetic influences between cognitive domains and psychiatric disorder risk based on genome-wide data

10.1101/2020.09.16.297408 ◽

2020 ◽

Author(s):

CE Carey ◽

Y Huang ◽

RW Strong ◽

S Aslibekyan ◽

RC Gentleman ◽

...

Keyword(s):

Psychiatric Disorder ◽

Genetic Correlation ◽

Cognitive Abilities ◽

Vocabulary Knowledge ◽

Digit Symbol ◽

Visual Change ◽

Genome Wide ◽

Symbol Substitution ◽

Visual Change Detection ◽

Disorder Risk

AbstractGroup-level cognitive performance differences are found in psychiatric disorders ranging from depression to autism to schizophrenia. To investigate the genetics of individual differences in fluid and crystallized cognitive abilities and their associations with psychiatric disorder risk, we conducted genome-wide association studies (GWAS) of a total of 335,227 consented 23andMe customers of European descent between the ages of 50 and 85, who completed at least one online test of crystallized cognitive ability (vocabulary knowledge, N=188,434) and/or fluid cognitive ability (visual change detection, N=158 888; digit-symbol substitution, N=132,807). All cognitive measures were significantly heritable (h2=0.10-0.16), and GWAS identified 25 novel genome-wide significant loci. Genetic correlation analyses highlight variable profiles of genetic relationships across tasks and disorders. While schizophrenia had moderate negative genetic correlations with tests of fluid cognition (visual change detection rg=−0.27, p<9.2e-24; digit-symbol substitution rg=−0.26, p<5.2e-27), it was only weakly negatively associated with crystalized cognition (vocabulary knowledge rg=−0.07, p<0.004). Autism, in contrast, showed a robust positive genetic correlation with vocabulary knowledge (rg=0.30, p<5.6e-13) and little to no genetic correlation with either fluid cognition task (rg’s<0.08, p’s>0.005). Crystalized and fluid cognitive abilities thus have correlated but distinct genetic architectures that relate to those of psychiatric disorders. Understanding the genetic underpinnings of specific cognitive abilities, and their relationships to psychiatric disorder risk, can inform the understanding of disease biology nosology and etiology.

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Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types

Science Advances ◽

10.1126/sciadv.abd9036 ◽

2021 ◽

Vol 7 (3) ◽

pp. eabd9036

Author(s):

Sara Saez-Atienzar ◽

Sara Bandres-Ciga ◽

Rebekah G. Langston ◽

Jonggeol J. Kim ◽

Shing Wan Choi ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Membrane Trafficking ◽

Molecular Mechanisms ◽

Cell Types ◽

Polygenic Risk Score ◽

Genome Wide ◽

Genome Wide Data ◽

Data Driven Approach ◽

Single Nucleus ◽

Lateral Sclerosis

Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely, neuron projection morphogenesis, membrane trafficking, and signal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated six differentially expressed genes (ATG16L2, ACSL5, MAP1LC3A, MAPKAPK3, PLXNB2, and SCFD1) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types.

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Ancient genomic time transect from the Central Asian Steppe unravels the history of the Scythians

Science Advances ◽

10.1126/sciadv.abe4414 ◽

2021 ◽

Vol 7 (13) ◽

pp. eabe4414

Author(s):

Guido Alberto Gnecchi-Ruscone ◽

Elmira Khussainova ◽

Nurzhibek Kahbatkyzy ◽

Lyazzat Musralina ◽

Maria A. Spyrou ◽

...

Keyword(s):

Bronze Age ◽

Iron Age ◽

Gene Pools ◽

Social Rules ◽

Eurasian Steppe ◽

Central Asian ◽

Genome Wide ◽

Genome Wide Data ◽

History Of ◽

First Millennium

The Scythians were a multitude of horse-warrior nomad cultures dwelling in the Eurasian steppe during the first millennium BCE. Because of the lack of first-hand written records, little is known about the origins and relations among the different cultures. To address these questions, we produced genome-wide data for 111 ancient individuals retrieved from 39 archaeological sites from the first millennia BCE and CE across the Central Asian Steppe. We uncovered major admixture events in the Late Bronze Age forming the genetic substratum for two main Iron Age gene-pools emerging around the Altai and the Urals respectively. Their demise was mirrored by new genetic turnovers, linked to the spread of the eastern nomad empires in the first centuries CE. Compared to the high genetic heterogeneity of the past, the homogenization of the present-day Kazakhs gene pool is notable, likely a result of 400 years of strict exogamous social rules.

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Genome diversity in Ukraine

GigaScience ◽

10.1093/gigascience/giaa159 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Taras K Oleksyk ◽

Walter W Wolfsberger ◽

Alexandra M Weber ◽

Khrystyna Shchubelka ◽

Olga T Oleksyk ◽

...

Keyword(s):

Sequence Data ◽

Copy Number Variations ◽

Genomic Variation ◽

High Coverage ◽

Genome Data ◽

New Information ◽

Genome Wide ◽

Public Data ◽

Genome Wide Data ◽

Multiple Samples

Abstract Background The main goal of this collaborative effort is to provide genome-wide data for the previously underrepresented population in Eastern Europe, and to provide cross-validation of the data from genome sequences and genotypes of the same individuals acquired by different technologies. We collected 97 genome-grade DNA samples from consented individuals representing major regions of Ukraine that were consented for public data release. BGISEQ-500 sequence data and genotypes by an Illumina GWAS chip were cross-validated on multiple samples and additionally referenced to 1 sample that has been resequenced by Illumina NovaSeq6000 S4 at high coverage. Results The genome data have been searched for genomic variation represented in this population, and a number of variants have been reported: large structural variants, indels, copy number variations, single-nucletide polymorphisms, and microsatellites. To our knowledge, this study provides the largest to-date survey of genetic variation in Ukraine, creating a public reference resource aiming to provide data for medical research in a large understudied population. Conclusions Our results indicate that the genetic diversity of the Ukrainian population is uniquely shaped by evolutionary and demographic forces and cannot be ignored in future genetic and biomedical studies. These data will contribute a wealth of new information bringing forth a wealth of novel, endemic and medically related alleles.

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Initial Upper Palaeolithic humans in Europe had recent Neanderthal ancestry

Nature ◽

10.1038/s41586-021-03335-3 ◽

2021 ◽

Vol 592 (7853) ◽

pp. 253-257 ◽

Cited By ~ 3

Author(s):

Mateja Hajdinjak ◽

Fabrizio Mafessoni ◽

Laurits Skov ◽

Benjamin Vernot ◽

Alexander Hübner ◽

...

Keyword(s):

Family History ◽

East Asia ◽

Late Pleistocene ◽

Modern Human ◽

Human Migration ◽

Upper Palaeolithic ◽

Modern Humans ◽

Genome Wide ◽

Genome Wide Data

AbstractModern humans appeared in Europe by at least 45,000 years ago1–5, but the extent of their interactions with Neanderthals, who disappeared by about 40,000 years ago6, and their relationship to the broader expansion of modern humans outside Africa are poorly understood. Here we present genome-wide data from three individuals dated to between 45,930 and 42,580 years ago from Bacho Kiro Cave, Bulgaria1,2. They are the earliest Late Pleistocene modern humans known to have been recovered in Europe so far, and were found in association with an Initial Upper Palaeolithic artefact assemblage. Unlike two previously studied individuals of similar ages from Romania7 and Siberia8 who did not contribute detectably to later populations, these individuals are more closely related to present-day and ancient populations in East Asia and the Americas than to later west Eurasian populations. This indicates that they belonged to a modern human migration into Europe that was not previously known from the genetic record, and provides evidence that there was at least some continuity between the earliest modern humans in Europe and later people in Eurasia. Moreover, we find that all three individuals had Neanderthal ancestors a few generations back in their family history, confirming that the first European modern humans mixed with Neanderthals and suggesting that such mixing could have been common.

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