We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009,P= 1.098 × 10⁻⁸) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40–60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 × 10⁻⁶) enrichment of associations at the gene level, forLOC388780(20p13; uncharacterized gene), and forVEPH1(3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20–25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (atp_T = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase;p = 8 × 10⁻¹³), bipolar disorder (1.53[1.44; 1.63];p = 1 × 10⁻⁴³), schizophrenia (1.36[1.28; 1.45];p = 4 × 10⁻²²), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30];p = 3 × 10⁻¹²), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96];p = 5 × 10⁻⁴), educational attainment (0.86[0.82; 0.91];p = 2 × 10⁻⁷), and intelligence (0.72[0.68; 0.76];p = 9 × 10⁻²⁹). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.

Genetic factors undoubtedly affect the development of congenital heart disease (CHD) but still remain ill defined. We sought to identify genetic risk factors associated with CHD and to accomplish a functional analysis of SNP-carrying genes. We performed a genome-wide association study (GWAS) of 4034 White patients with CHD and 8486 healthy controls. One SNP on chromosome 5q22.2 reached genome-wide significance across all CHD phenotypes and was also indicative for septal defects. One region on chromosome 20p12.1 pointing to the MACROD2 locus identified 4 highly significant SNPs in patients with transposition of the great arteries (TGA). Three highly significant risk variants on chromosome 17q21.32 within the GOSR2 locus were detected in patients with anomalies of thoracic arteries and veins (ATAV). Genetic variants associated with ATAV are suggested to influence the expression of WNT3, and the variant rs870142 related to septal defects is proposed to influence the expression of MSX1. We analyzed the expression of all 4 genes during cardiac differentiation of human and murine induced pluripotent stem cells in vitro and by single-cell RNA-Seq analyses of developing murine and human hearts. Our data show that MACROD2, GOSR2, WNT3, and MSX1 play an essential functional role in heart development at the embryonic and newborn stages.

Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562–3468). We observed a genome-wide significant effect (p < 1 × 10⁻⁸) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10⁻⁹), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10⁻⁸). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10⁻⁸) and with all the cognitive traits tested (p = 3.07 × 10⁻⁸), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10⁻⁵–10⁻⁷]) and negatively associated with ADHD PRS (p ~ [10⁻⁸−10⁻¹⁷]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.

Severe stress exposure increases the risk of stress-related disorders such as major depressive disorder (MDD). An essential characteristic of MDD is the impairment of social functioning and lack of social motivation. Chronic social defeat stress is an established animal model for MDD research, which induces a cascade of physiological and behavioral changes. Current markerless pose estimation tools allow for more complex and naturalistic behavioral tests. Here, we introduce the open-source tool DeepOF to investigate the individual and social behavioral profile in mice by providing supervised and unsupervised pipelines using DeepLabCut-annotated pose estimation data. Applying this tool to chronic social defeat in male mice, the DeepOF supervised and unsupervised pipelines detect a distinct stress-induced social behavioral pattern, which was particularly observed at the beginning of a novel social encounter and fades with time due to habituation. In addition, while the classical social avoidance task does identify the stress-induced social behavioral differences, both DeepOF behavioral pipelines provide a clearer and more detailed profile. Moreover, DeepOF aims to facilitate reproducibility and unification of behavioral classification by providing an open-source tool, which can advance the study of rodent individual and social behavior, thereby enabling biological insights and, for example, subsequent drug development for psychiatric disorders.