👤 Danielle Posthuma

Investigating the genetic underpinnings of functional brain connectivity is essential to understand how genetic variation influences brain health and disease. Here, a mass-univariate approach was adopted to study the genetic architecture of functional brain circuitry (N Show less

Many drug targets in ongoing Parkinson's disease (PD) clinical trials have strong genetic links. While genome-wide association studies (GWAS) nominate regions associated with disease, pinpointing causal genes is challenging. Our aim was to prioritize additional druggable genes underlying PD GWAS signals. The polygenic priority score (PoPS) integrates genome-wide information from MAGMA gene-level associations and over 57,000 gene-level features. We applied PoPS to East Asian and European PD GWAS data and prioritized genes based on PoPS, distance to the GWAS signal, and non-synonymous credible set variants. We prioritized 46 genes, including well-established PD genes (SNCA, LRRK2, GBA1, TMEM175, VPS13C), genes with strong literature evidence supporting a mechanistic link to PD (RIT2, BAG3, SCARB2, FYN, DYRK1A, NOD2, CTSB, SV2C, ITPKB), and genes relatively unexplored in PD. Many hold potential for drug repurposing or development. We prioritized high-confidence genes with strong links to PD pathogenesis that may represent our next-best candidates for developing disease-modifying therapeutics. Show less

Recent advancements in Parkinson's disease (PD) drug development have been significantly driven by genetic research. Importantly, drugs supported by genetic evidence are more likely to be approved. While genome-wide association studies (GWAS) are a powerful tool to nominate genomic regions associated with certain traits or diseases, pinpointing the causal biologically relevant gene is often challenging. Our aim was to prioritize genes underlying PD GWAS signals. The polygenic priority score (PoPS) is a similarity-based gene prioritization method that integrates genome-wide information from MAGMA gene-level association tests and more than 57,000 gene-level features, including gene expression, biological pathways, and protein-protein interactions. We applied PoPS to data from the largest published PD GWAS in East Asian- and European-ancestries. We identified 120 independent associations with Show less

In this study we aimed to establish the genetic cause of a myriad of cardiovascular defects prevalent in individuals from a genetically isolated population, who were found to share a common ancestor in 1728. Trio genome sequencing was carried out in an index patient with critical congenital heart disease (CHD); family members had either exome or Sanger sequencing. To confirm enrichment, we performed a gene-based association test and meta-analysis in two independent validation cohorts: one with 2685 CHD cases versus 4370 . These controls were also ancestry-matched (same as FTAA controls), and the other with 326 cases with familial thoracic aortic aneurysms (FTAA) and dissections versus 570 ancestry-matched controls. Functional consequences of identified variants were evaluated using expression studies. We identified a loss-of-function variant in the Notch target transcription factor-encoding gene HEY2. The homozygous state (n = 3) causes life-threatening congenital heart defects, while 80% of heterozygous carriers (n = 20) had cardiovascular defects, mainly CHD and FTAA of the ascending aorta. We confirm enrichment of rare risk variants in HEY2 functional domains after meta-analysis (MetaSKAT p = 0.018). Furthermore, we show that several identified variants lead to dysregulation of repression by HEY2. A homozygous germline loss-of-function variant in HEY2 leads to critical CHD. The majority of heterozygotes show a myriad of cardiovascular defects. Show less

Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10 Show less

Multiple lines of evidence suggest that fatty acids (FA) play an important role in cognitive function. However, little is known about the functional genetic pathways involved in cognition. The main goals of this study were to replicate previously reported interaction effects between breast feeding (BF) and FA desaturase (FADS) genetic variation on IQ and to investigate the possible mechanisms by which these variants might moderate BF effect, focusing on brain expression. Using a sample of 534 twins, we observed a trend in the moderation of BF effects on IQ by FADS2 variation. In addition, we made use of publicly available gene expression databases from both humans (193) and mice (93) and showed that FADS2 variants also correlate with FADS1 brain expression (P-value<1.1E-03). Our results provide novel clues for the understanding of the genetic mechanisms regulating FA brain expression and improve the current knowledge of the FADS moderation effect on cognition. Show less

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes. Show less