The genetics of sexual orientation: Twin studies and other analyses of inheritance of sexual orientation in humans has indicated that same-sex sexual behavior has a genetic component. Previous searches for the specific genes involved have been underpowered and thus unable to detect genetic signals. Ganna et al. perform a genome-wide association study on 493,001 participants from the United States, the United Kingdom, and Sweden to study genes associated with sexual orientation (see the Perspective by Mills). They find multiple loci implicated in same-sex sexual behavior indicating that, like other behavioral traits, nonheterosexual behavior is polygenic. Science , this issue p. eaat7693 ; see also p. 869

Background: Findings from family and twin studies support a genetic contribution to the development of sexual orientation in men. However, previous studies have yielded conflicting evidence for linkage to chromosome Xq28.Method: We conducted a genome-wide linkage scan on 409 independent pairs of homosexual brothers (908 analyzed individuals in 384 families), by far the largest study of its kind to date.Results: We identified two regions of linkage: the pericentromeric region on chromosome 8 (maximum two-point LOD = 4.08, maximum multipoint LOD = 2.59), which overlaps with the second strongest region from a previous separate linkage scan of 155 brother pairs; and Xq28 (maximum two-point LOD = 2.99, maximum multipoint LOD = 2.76), which was also implicated in prior research.Conclusions: Results, especially in the context of past studies, support the existence of genes on pericentromeric chromosome 8 and chromosome Xq28 influencing development of male sexual orientation.

Effects of allele-specific open chromatin: Genetic variants in noncoding regions of the genome may underlie the development of disease. However, we are just beginning to tease apart the function of such variants associated with neuropsychiatric disease. Using five types of neural progenitor cells derived from 20 human induced pluripotent stem cell lines, Zhang et al. looked at allele-specific open chromatin (ASoC) variants. Many ASoC variants overlapped with genomic elements, such as transcription factor binding sites, and loci identified in genome-wide association studies for neurological traits. From the experimental and computational analyses, they identified single-nucleotide polymorphisms and illuminate how one schizophrenia-associated variant affects neurodevelopment. Science , this issue p. 561

Schizophrenia genome-wide association studies (GWAS) have identified common SNPs, rare copy number variants (CNVs) and a large polygenic contribution to illness risk, but biological mechanisms remain unclear. Bioinformatic analyses of significantly associated genetic variants point to a large role for regulatory variants. To identify gene expression abnormalities in schizophrenia, we generated whole-genome gene expression profiles using microarrays on lymphoblastoid cell lines (LCLs) from 413 cases and 446 controls. Regression analysis identified 95 transcripts differentially expressed by affection status at a genome-wide false discovery rate (FDR) of 0.05, while simultaneously controlling for confounding effects. These transcripts represented 89 genes with functions such as neurotransmission, gene regulation, cell cycle progression, differentiation, apoptosis, microRNA (miRNA) processing and immunity. This functional diversity is consistent with schizophrenia's likely significant pathophysiological heterogeneity. The overall enrichment of immune-related genes among those differentially expressed by affection status is consistent with hypothesized immune contributions to schizophrenia risk. The observed differential expression of extended major histocompatibility complex (xMHC) region histones (HIST1H2BD, HIST1H2BC, HIST1H2BH, HIST1H2BG and HIST1H4K) converges with the genetic evidence from GWAS, which find the xMHC to be the most significant susceptibility locus. Among the differentially expressed immune-related genes, B3GNT2 is implicated in autoimmune disorders previously tied to schizophrenia risk (rheumatoid arthritis and Graves’ disease), and DICER1 is pivotal in miRNA processing potentially linking to miRNA alterations in schizophrenia (e.g. MIR137, the second strongest GWAS finding). Our analysis provides novel candidate genes for further study to assess their potential contribution to schizophrenia.