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Diabetes is a multifactorial disease, caused by a complex interplay between environmental and genetic risk factors. Genetic determinants of particularly type 1 diabetes (T1D) and type 2 diabetes (T2D) have been studied extensively, whereas well-powered studies of latent autoimmune diabetes in adults (LADA) are lacking. So far available studies support a clear genetic overlap between LADA and T1D, however, with smaller effect sizes of the T1D-risk variants in LADA as compared to T1D. A genetic overlap between LADA and T2D is less clear. However, recent studies, including large numbers of LADA patients, provide different lines of evidence to support a genetic overlap between T2D and LADA. The genetic predisposition to LADA is yet to be explored in a study design, like a genome-wide association study, which allows for analyses of the genetic predisposition independently of prior hypothesis about potential candidate genes. This type of study may facilitate the discovery of risk variants associated with LADA independently of T1D and T2D, and is central in order to determine if LADA should be considered as an independent diabetic subtype. Extended knowledge about the genetic predisposition to LADA may also facilitate stratification of the heterogeneous group of LADA patients, which may assist the choice of treatment. This mini-review summarizes current knowledge of the genetics of LADA, and discusses the perspectives for future studies.

In this mini-review, we give an overview of what is known about the genetic architecture of obesity and related metabolic traits with a primary focus on recent insights from studies of historically small and isolated populations. We start by briefly explaining what genetic architecture is and why studies of isolated populations in general are valuable if we want a complete picture of the genetic architecture of diseases and other traits among humans. Then we contrast what is known about the genetic architecture of obesity and related metabolic traits among large outbred populations, like Europeans, with results from recent studies of isolated populations. Finally, we briefly discuss the perspectives of studying isolated populations to gain insight into genetic architecture in humans.

We have identified a variant in ADCY3 (encoding adenylate cyclase 3) associated with markedly increased risk of obesity and type 2 diabetes in the Greenlandic population. The variant disrupts a splice acceptor site, and carriers have decreased ADCY3 RNA expression. Additionally, we observe an enrichment of rare ADCY3 loss-of-function variants among individuals with type 2 diabetes in trans-ancestry cohorts. These findings provide new information on disease etiology relevant for future treatment strategies.

Patients with germline mutations in SMAD4 can present symptoms of both juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT): the JP-HHT syndrome. The complete phenotypic picture of this syndrome is only just emerging. We describe the clinical characteristics of 14 patients with SMAD4-mutations. The study was a retrospective, register-based study. SMAD4 mutations carriers were identified through the Danish HHT-registry, the genetic laboratories - and the genetic departments in Denmark. The medical files from relevant departments were reviewed and symptoms of HHT, JPS, aortopathy and family history were noted. We detected 14 patients with SMAD4 mutations. All patients had polyps removed and 11 of 14 fulfilled the diagnostic criteria for JPS. Eight patients were screened for HHT-symptoms and seven of these fulfilled the Curaçao criteria. One patient had aortic root dilation. Our findings support that SMAD4 mutations carriers have symptoms of both HHT and JPS and that the frequency of PAVM and gastric involvement with polyps is higher than in patients with HHT or JPS not caused by a SMAD4 mutation. Out of eight patients screened for aortopathy, one had aortic root dilatation, highlighting the need for additional screening for aortopathy.

Since 2007, discovery of genetic variants associated with general obesity and fat distribution has advanced tremendously through genome-wide association studies (GWAS). Currently, the number of robustly associated loci is 190. Even though these loci explain <3 % of the variance, they have provided us a still emerging picture of genomic localization, frequency and effect size spectra, and hints of functional implications. The translation into biological knowledge has turned out to be an immense task. However, in silico enrichment analyses of genes involved in specific pathways or expressed in specific tissues have the power to suggest biological mechanisms underlying obesity. Inspired by this, we highlight genes in five loci potentially mechanistically linked to leptin-receptor trafficking and signaling in primary cilia. The clinical application of genetic knowledge as prediction, prevention, or treatment strategies is unfortunately still far from reality. Thus, despite major advances, further research is warranted to solve one of the greatest health problems in modern society.