Biology subjects

Lam, M.

Publications and source records attributed to Lam, M..

5 recordsLinked to original sources

bioRxiv2018

Comparative genetic architectures of schizophrenia in East Asian and European populations

Author summarySchizophrenia is a severe psychiatric disorder with a lifetime risk of about 1% world-wide. Most large schizophrenia genetic studies have studied people of primarily European ancestry, potentially missing important biological insights. Here we present a study of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide significant schizophrenia associations in 19 genetic loci. Over the genome, the common genetic variants that confer risk for schizophrenia have highly similar effects in those of East Asian and European ancestry (rg=0.98), indicating for the first time that the genetic basis of schizophrenia and its biology are broadly shared across these world populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries revealed 208 genome-wide significant schizophrenia associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping more precisely isolated schizophrenia causal alleles in 70% of these loci. Despite consistent genetic effects across populations, polygenic risk models trained in one population have reduced performance in the other, highlighting the importance of including all major ancestral groups with sufficient sample size to ensure the findings have maximum relevance for all populations.

genetics↗

bioRxiv2018

Genome Wide Study of Tardive Dyskinesia in Schizophrenia

Tardive dyskinesia (TD) is a severe condition characterized by repetitive involuntary movement of orofacial regions and extremities. Patients treated with antipsychotics typically present with TD symptomatology. Here, we conducted the largest GWAS of TD to date, by meta-analyzing samples of East-Asian, European, and African-American ancestry, followed by analyses of biological pathways and polygenic risk with related phenotypes. We identified a novel locus and three suggestive loci, implicating immune-related pathways. Through integrating trans-ethnic fine-mapping, we identified putative credible causal variants for three of the loci. Multivariate analyses of polygenic risk for TD supports the genetic susceptibility of TD, with relatively lower allele frequencies variants being associated with TD, beyond that of antipsychotic medication. Together, these findings provide new insights into the genetic architecture and biology of TD.

genomics↗

bioRxiv2017

GWAS meta-analysis (N=279,930) identifies new genes and functional links to intelligence

Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present the largest genetic association study of intelligence to date (N=279,930), identifying 206 genomic loci (191 novel) and implicating 1,041 genes (963 novel) 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 identify 89 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain and specifically in striatal medium spiny neurons and cortical and hippocampal pyramidal neurons. Gene-set analyses implicate pathways related to neurogenesis, neuron differentiation and synaptic structure. We confirm previous strong genetic correlations with several neuropsychiatric disorders, and Mendelian Randomization results suggest protective effects of intelligence for Alzheimers dementia and ADHD, and bidirectional causation with strong pleiotropy for schizophrenia. These results are a major step forward in understanding the neurobiology of intelligence as well as genetically associated neuropsychiatric traits.

genetics↗

bioRxiv2017

Ninety-nine independent genetic loci influencing general cognitive function include genes associated with brain health and structure (N = 280,360)

General cognitive function is a prominent human trait associated with many important life outcomes1,2, including longevity3. The substantial heritability of general cognitive function is known to be polygenic, but it has had little explication in terms of the contributing genetic variants4,5,6. Here, we combined cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N=280,360; age range = 16 to 102). We found 9,714 genome-wide significant SNPs (P<5 x 10-8) in 99 independent loci. Most showed clear evidence of functional importance. Among many novel genes associated with general cognitive function were SGCZ, ATXN1, MAPT, AUTS2, and P2RY6. Within the novel genetic loci were variants associated with neurodegenerative disorders, neurodevelopmental disorders, physical and psychiatric illnesses, brain structure, and BMI. Gene-based analyses found 536 genes significantly associated with general cognitive function; many were highly expressed in the brain, and associated with neurogenesis and dendrite gene sets. Genetic association results predicted up to 4% of general cognitive function variance in independent samples. There was significant genetic overlap between general cognitive function and information processing speed, as well as many health variables including longevity.

genetics↗

bioRxiv2017

Large-Scale cognitive GWAS Meta-analysis Reveals Tissue-Specific Neural Expression and Potential Nootopic Drug Targets

Neurocognitive ability is a fundamental readout of brain function, and cognitive deficits are a critical component of neuropsychiatric disorders, yet neurocognition is poorly understood at the molecular level. In the present report, we present the largest genome-wide association studies (GWAS) of cognitive ability to date (N=107,207), and further enhance signal by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with cognitive ability, 34 of which were novel. A total of 350 genes were implicated, and this list showed significant enrichment for genes associated with Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis of gene results implicated the biological process of neurogenesis, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker; and LY97241, a potassium channel inhibitor. Transcriptome-wide analysis revealed that the implicated genes were strongly expressed in neurons, but not astrocytes or oligodendrocytes, and were more strongly associated with fetal brain expression than adult brain expression. Several tissue-specific gene expression relationships to cognitive ability were observed (for example, DAG1 levels in the hippocampus). Finally, we report novel genetic correlations between cognitive ability and disparate phenotypes such as maternal age at first birth and number of children, as well as several autoimmune disorders.

genomics↗