Previous genome-wide association studies (GWASs) for adiponectin, a complex trait linked to type 2 diabetes and obesity, identified >20 associated loci. However, most loci were identified in populatio Show more
Previous genome-wide association studies (GWASs) for adiponectin, a complex trait linked to type 2 diabetes and obesity, identified >20 associated loci. However, most loci were identified in populations of European ancestry, and many of the target genes underlying the associations remain unknown. We conducted a cross-ancestry adiponectin GWAS meta-analysis in ≤46,434 individuals from the Metabolic Syndrome in Men (METSIM) cohort and the ADIPOGen and AGEN consortiums. We combined study-specific association summary statistics using a fixed-effects, inverse variance-weighted approach. We identified 22 loci associated with adiponectin (p < 5×10 Show less
Alternate splicing events can create isoforms that alter gene function, and genetic variants associated with alternate gene isoforms may reveal molecular mechanisms of disease. We used subcutaneous ad Show more
Alternate splicing events can create isoforms that alter gene function, and genetic variants associated with alternate gene isoforms may reveal molecular mechanisms of disease. We used subcutaneous adipose tissue of 426 Finnish men from the METSIM study and identified splice junction quantitative trait loci (sQTLs) for 6,077 splice junctions (FDR < 1%). In the same individuals, we detected expression QTLs (eQTLs) for 59,443 exons and 15,397 genes (FDR < 1%). We identified 595 genes with an sQTL and exon eQTL but no gene eQTL, which could indicate potential isoform differences. Of the significant sQTL signals, 2,114 (39.8%) included at least one proxy variant (linkage disequilibrium r Show less
Structural brain changes along the lineage leading to modern Homo sapiens contributed to our distinctive cognitive and social abilities. However, the evolutionarily relevant molecular variants impacti Show more
Structural brain changes along the lineage leading to modern Homo sapiens contributed to our distinctive cognitive and social abilities. However, the evolutionarily relevant molecular variants impacting key aspects of neuroanatomy are largely unknown. Here, we integrate evolutionary annotations of the genome at diverse timescales with common variant associations from large-scale neuroimaging genetic screens. We find that alleles with evidence of recent positive polygenic selection over the past 2000-3000 years are associated with increased surface area (SA) of the entire cortex, as well as specific regions, including those involved in spoken language and visual processing. Therefore, polygenic selective pressures impact the structure of specific cortical areas even over relatively recent timescales. Moreover, common sequence variation within human gained enhancers active in the prenatal cortex is associated with postnatal global SA. We show that such variation modulates the function of a regulatory element of the developmentally relevant transcription factor HEY2 in human neural progenitor cells and is associated with structural changes in the inferior frontal cortex. These results indicate that non-coding genomic regions active during prenatal cortical development are involved in the evolution of human brain structure and identify novel regulatory elements and genes impacting modern human brain structure. Show less