As we have often presented in these GEITP pages, we report here two HEROIC (large) genome-wide association studies (GWAS), which represent huge populations (cohorts) examined for DNA-sequence differences (virtually anywhere in the genome) that appear to be associated with a multifactorial trait (i.e. a phenotype that reflects the contribution of hundreds, possibly thousands, of genes, + epigenetic effects, + environmental factors). In this case, the intriguing/controversial “traits’ being studied are INTELLIGENCE and NEUROTICISM.
Intelligence is known to be highly heritable, as well as being a major determinant of human health and well-being. Five recent GWAS meta-analyses had identified 24 genomic loci (loci = locations in the DNA sequence) linked to variations in intelligence –– but much more information underlying fundamental genetic contributions remains to be uncovered. Authors [see first attached file] present a large-scale GWAS 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.
The associated genes identified were strongly expressed in the brain –– specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene-set analyses implicate pathways related to central nervous system (CNS) development, and synaptic structure. These exciting data confirm previous strong genetic correlations with multiple health-related outcomes. Mendelian-randomization-analysis results suggest protective effects of intelligence for Alzheimer disease, and attention-deficit-hyperactivity disorder (ADHD), and bidirectional causation with pleiotropic effects (i.e. when one gene influences two or more seemingly unrelated traits) for schizophrenia. These results represent an important step forward in understanding the neurobiology of cognitive function (i.e. psychological processes involved in acquisition and understanding of knowledge, formation of beliefs and attitudes, and rational decision-making and problem-solving –– traits that seem to be lacking in today’s politics, worldwide), as well as genetically related neurological and psychiatric disorders.
Neuroticism is an important risk factor for psychiatric traits –– including major depressive order (MDD), anxiety, and schizophrenia. At the time of analysis, six previous GWAS had reported 16 genomic loci associated with neuroticism. Authors [see second attached file] conducted a huge GWAS meta-analysis (N= 449,484) of neuroticism and identified 136 independent genome-wide significant loci (124 new), which implicate 599 genes. Functional follow-up analyses showed enrichment in several brain regions, and involvement of specific cell-types, including dopamine-producing neuroblasts, medium spiny neurons, and serotonin-producing neurons.
Gene-set analyses implicated three specific pathways: neurogenesis, behavioral response-to-cocaine processes, and axon portion (in vertebrates, the long slender projection of a nerve cell, or neuron, that typically conducts electrical impulses known as ‘action potentials’, away from the nerve-cell body). Authors show that neuroticism’s genetic signal originates, in part, in two genetically distinguishable subclusters (‘depressed affect ’ and ‘worry ’) –– suggesting distinct causal mechanisms for subtypes of individuals. Mendelian-randomization analysis showed uni-directional and bi-directional effects between neuroticism and multiple psychiatric traits. These exciting findings enhance our neurobiological understanding of neuroticism and provide specific leads for functional follow-up experiments. 🙂
DwN
Nature Genetics Jul 2o18; 50: 912–919 & 920–927