Yunpeng Wang
Profile Url: yunpeng-wang
Researcher at University of Oslo
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Nature Communications, 2019-06-03
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Nature Communications
Accumulating evidence from genome wide association studies (GWAS) suggests an abundance of shared genetic influences among complex human traits and disorders, such as mental disorders. While current cross-trait analytical methods focus on genetic correlation between traits, we developed a novel statistical tool (MiXeR), which quantifies polygenic overlap independent of genetic correlation, using summary statistics from GWAS. MiXeR results can be presented as a Venn diagram of unique and shared polygenic components across traits. At 90% of SNP-heritability explained for each phenotype, MiXeR estimates that more than 9K variants causally influence schizophrenia, 7K influence bipolar disorder, and out of those variants 6.9K are shared between these two disorders, which have high genetic correlation. Further, MiXeR uncovers extensive polygenic overlap between schizophrenia and educational attainment. Despite a genetic correlation close to zero, these traits share more than 9K causal variants, while 3K additional variants only influence educational attainment. By considering the polygenicity, heritability and discoverability of complex phenotypes, MiXeR provides a more complete quantification of shared genetic architecture than offered by other available tools.
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European Journal of Human Genetics, 2018-04-27
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European Journal of Human Genetics
Cognitive and brain development are determined by dynamic interactions between genes and environment across the lifespan. Aside from marker-by-marker analyses of polymorphisms, biologically meaningful features of the whole-genome (derived from the combined effect of individual markers) have been postulated to inform on human phenotypes including cognitive traits and their underlying biological substrate. Here, estimates of inbreeding and genetic susceptibility for schizophrenia calculated from genome-wide data -runs of homozygosity (ROH) and schizophrenia polygenic risk score (PGRS)- are analyzed in relation to cognitive abilities (n=4183) and brain structure (n=516) in a general-population sample of European-ancestry participants aged 8-22, from the Philadelphia Neurodevelopmental Cohort. The findings suggest that a higher ROH burden and higher schizophrenia PGRS are associated with higher intelligence. Cognition~ROH and cognition~PGRS associations obtained in this cohort may respectively evidence that assortative mating influences intelligence, and that individuals with high schizophrenia genetic risk who do not transition to disease status are cognitively resilient. Neuroanatomical data showed that the effects of schizophrenia PGRS on cognition could be modulated by brain structure, although larger imaging datasets are needed to accurately disentangle the underlying neural mechanisms linking IQ with both inbreeding and the genetic burden for schizophrenia.
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PLOS Medicine, 2017-03-21
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PLOS Medicine
Importance: Identifying individuals at risk for developing Alzheimers disease (AD) is of utmost importance. Although genetic studies have identified APOE and other AD associated single nucleotide polymorphisms (SNPs), genetic information has not been integrated into an epidemiological framework for personalized risk prediction. Objective: To develop, replicate and validate a novel polygenic hazard score for predicting age-specific risk for AD. Setting: Multi-center, multi-cohort genetic and clinical data. Participants: We assessed genetic data from 17,008 AD patients and 37,154 controls from the International Genetics of Alzheimers Project (IGAP), and 6,409 AD patients and 9,386 older controls from Phase 1 Alzheimers Disease Genetics Consortium (ADGC). As independent replication and validation cohorts, we also evaluated genetic, neuroimaging, neuropathologic, CSF and clinical data from ADGC Phase 2, National Institute of Aging Alzheimers Disease Center (NIA ADC) and Alzheimers Disease Neuroimaging Initiative (ADNI) (total n = 20,680) Main Outcome(s) and Measure(s): Use the IGAP cohort to first identify AD associated SNPs (at p < 10-5). Next, integrate these AD associated SNPs into a Cox proportional hazards model using ADGC phase 1 genetic data, providing a polygenic hazard score (PHS) for each participant. Combine population based incidence rates, and genotype-derived PHS for each individual to derive estimates of instantaneous risk for developing AD, based on genotype and age. Finally, assess replication and validation of PHS in independent cohorts. Results: Individuals in the highest PHS quantiles developed AD at a considerably lower age and had the highest yearly AD incidence rate. Among APOE 3/3 individuals, PHS modified expected age of AD onset by more than 10 years between the lowest and highest deciles. In independent cohorts, PHS strongly predicted empirical age of AD onset (p = 1.1 x 10-26), longitudinal progression from normal aging to AD (p = 1.54 x 10-10) and associated with markers of AD neurodegeneration. Conclusions: We developed, replicated and validated a clinically usable PHS for quantifying individual differences in age-specific risk of AD. Beyond APOE, polygenic architecture plays an important role in modifying AD risk. Precise quantification of AD genetic risk will be useful for early diagnosis and therapeutic strategies.
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Science, 2020-03-19
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Science
The cerebral cortex underlies our complex cognitive capabilities, yet we know little about the specific genetic loci influencing human cortical structure. To identify genetic variants, including structural variants, impacting cortical structure, we conducted a genome-wide association meta-analysis of brain MRI data from 51,662 individuals. We analysed the surface area and average thickness of the whole cortex and 34 regions with known functional specialisations. We identified 255 nominally significant loci ( P ≤ 5 × 10−8); 199 survived multiple testing correction ( P ≤ 8.3 × 10−10; 187 surface area; 12 thickness). We found significant enrichment for loci influencing total surface area within regulatory elements active during prenatal cortical development, supporting the radial unit hypothesis. Loci impacting regional surface area cluster near genes in Wnt signalling pathways, known to influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson’s disease, insomnia, depression and ADHD. One Sentence Summary Common genetic variation is associated with inter-individual variation in the structure of the human cortex, both globally and within specific regions, and is shared with genetic risk factors for some neuropsychiatric disorders.
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SI
While development and aging of the cerebral cortex show a similar topographic organization and are mainly governed by the same genes, it is unclear whether the same is true for subcortical structures, which follow fundamentally different ontogenetic and phylogenetic principles than the cerebral cortex. To test the hypothesis that genetically governed neurodevelopmental processes can be traced in subcortical structures throughout life, we analyzed a longitudinal magnetic resonance imaging dataset (n = 974, age 4-89 years), identifying five clusters of longitudinal change in development. With some exceptions, these clusters followed placement along the cranial axis in embryonic brain development, suggesting continuity in the pattern of change from prenatal stages. Developmental change patterns were conserved through the lifespan and predicted general cognitive function in an age-invariant manner. The results were replicated in longitudinal data from the Lifebrain consortium (n = 756, age 19-83 years). Genetic contributions to longitudinal brain changes were calculated from the Vietnam Era Twin Study of Aging (n = 331 male twins, age 51-60 years), revealing that distinct sets of genes tended to govern change for each developmental cluster. This finding was confirmed with single nucleotide polymorphisms and cross-sectional MRI data from the UK Biobank (n = 20,588, age 40-69), demonstrating significantly higher co-heritability among structures belonging to the same developmental clusters. Together, these results suggest that coordination of subcortical change adheres to fundamental principles of lifespan continuity, genetic organization and age-invariant relationships to cognitive function. ### Competing Interest Statement The authors have declared no competing interest.
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The radial unit hypothesis provides a framework for global (proliferation) and regional (distribution) expansion of the primate cerebral cortex. Using principal component analysis (PCA), we have identified cortical regions with shared variance in their surface area and cortical thickness, respectively, segmented from magnetic resonance images obtained in 23,800 participants. We then carried out meta-analyses of genome-wide association studies of the first two principal components for each phenotype. For surface area (but not cortical thickness), we have detected strong associations between each of the components and single nucleotide polymorphisms in a number of gene loci. The first (global) component was associated mainly with loci on chromosome 17 (9.5e-32 ≤ p ≤ 2.8e-10), including those detected previously as linked with intracranial volume and/or general cognitive function. The second (regional) component captured shared variation in the surface area of the primary and adjacent secondary visual cortices and showed a robust association with polymorphisms in a locus on chromosome 14 containing Disheveled Associated Activator of Morphogenesis 1 ( DAAM1 ; p =2.4e-34). DAAM1 is a key component in the planar-cell-polarity signaling pathway. In follow-up studies, we have focused on the latter finding and established that: (1) DAAM1 is highly expressed between 12th and 22nd post-conception weeks in the human cerebral cortex; (2) genes co-expressed with DAAM1 in the primary visual cortex are enriched in mitochondria-related pathways; and (3) volume of the lateral geniculate nucleus, which projects to regions of the visual cortex staining for cytochrome oxidase (a mitochondrial enzyme), correlates with the surface area of the visual cortex in major-allele homozygotes but not in carriers of the minor allele. Altogether, we speculate that, in concert with thalamocortical input to cortical subplate, DAAM1 enables migration of neurons to cytochrome-oxidase rich regions of the visual cortex, and, in turn, facilitates regional expansion of this set of cortical regions during development.
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