A genome-wide scan was performed, using nonparametric linkage analyses, to find susceptibility loci for type 2 diabetes mellitus in the Dutch population. We studied 178 families from The Netherlands, who constituted 312 affected sibling pairs. The first stage of the genome scan consisted of 270 DNA markers, with an average intermarker spacing of 13 cM. Because obesity and type 2 diabetes mellitus are interrelated, the data set was stratified for the subphenotype body mass index, corrected for age and gender. This resulted in a suggestive maximum multipoint LOD score of 2.3 (single-point P value, 9.7 x 10(-4); genome-wide P value, 0.028) for the most obese 20% pedigrees of the data set, between marker loci D18S471 and D18S843. In the lowest 80% obese pedigrees, two interesting loci on chromosome 2 and 19 were found, with LOD scores of 1.5 and 1.3. We provide independent evidence that the chromosome 18p11 locus, reported earlier from a Finnish/Swedish population, is of definite interest for type 2 diabetes mellitus in connection with obesity. Subsequently, our results indicate that two novel loci may reside on chromosomes 2 and 19, with minor effects involved in the development of type 2 diabetes mellitus in the Dutch population.

Previously, we identified a locus on 11p influencing obesity in families with type 2 diabetes. Based on mouse studies, we selected TUB as a functional candidate gene and performed association studies to determine whether this controls obesity. We analyzed the genotypes of 13 single nucleotide polymorphisms (SNPs) around TUB in 492 unrelated type 2 diabetic patients with known BMI values. One SNP (rs1528133) was found to have a significant effect on BMI (1.54 kg/m 2 , P ‫؍‬ 0.006). This association was confirmed in a population enriched for type 2 diabetes, using 750 individuals who were not selected for type 2 diabetes. Two SNPs in linkage disequilibrium with rs1528133 and mapping to the 3 end of TUB, rs2272382, and rs2272383 also affected BMI by 1.3 kg/m2 (P ‫؍‬ 0.016 and P ‫؍‬ 0.010, respectively). Combined analysis confirmed this association (P ‫؍‬ 0.005 and P ‫؍‬ 0.002, respectively). Moreover, comparing 349 obese subjects (BMI >30 kg/m 2 ) from the combined cohort with 289 normal subjects (BMI <25 kg/m 2 ) revealed that the protective alleles have a lower frequency in obese subjects (odds ratio 1.32 [95% CI 1.04 -1.67], P ‫؍‬ 0.022). Altogether, data from the tubby mouse as well as these data suggest that TUB could be an important factor in controlling the central regulation of body weight in humans. Diabetes 55:385-389, 2006

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Res. 2003;11:1290 -1294. To study genetic loci influencing obesity in nuclear families with type 2 diabetes, we performed a genome-wide screen with 325 microsatellite markers that had an average spacing of 11 cM and a mean heterozygosity of ϳ75% covering all 22 autosomes. Genotype data were obtained from 562 individuals from 178 families from the Breda Study Cohort. These families were determined to have at least two members with type 2 diabetes. As a measure of obesity, the BMI of each diabetes patient was determined. The genotypes were analyzed using variance components (VCs) analysis implemented in GENEHUNTER 2 to determine quantitative trait loci influencing BMI. The VC analysis revealed two genomic regions showing VC logarithm of odds (LOD) scores Ն1.0 on chromosome 1 and chromosome 11. The regions of interest on both chromosomes were further investigated by fine-mapping with additional markers, resulting in a VC LOD score of 1.5 on chromosome 1q and a VC LOD of 2.4 on chromosome 11q. The locus on chromosome 1 has been implicated previously in diabetes. The locus on chromosome 11 has been implicated previously in diabetes and obesity. Our study to determine linkage for BMI confirms the presence of quantitative trait loci influencing obesity in subjects with type 2 diabetes on chromosomes 1q31-q42 and 11q14-q24. Key words: type 2 diabetes, genome-wide screening, quantitative trait loci, geneticsThe etiology of type 2 diabetes is ill defined: several studies indicate that the disease results from a combination of genetic susceptibility and external risk factors (1). According to this multifactorial model, genetically predisposed subjects will not necessarily develop overt disease unless they are also exposed to particular environmental factors (2). Important risk factors for the development of type 2 diabetes include a family history of diabetes, advanced age, hypertension, lack of physical exercise, and obesity (1).Obesity, like diabetes, is a complex trait determined by multiple genetic and environmental factors (including physiological, behavioral, and sociocultural factors) (3). In recent years, several single-gene defects responsible for obesity in rodents, and also in humans in rare instances of extended families, have been identified. In addition to leptin (Online Mendelian Inheritance in Man no. 164160), which is the most notable example, numerous other proteins and neuropeptides have recently been found to participate in a complex network regulating food intake and energy expenditure (4). The relationship between type 2 diabetes and obesity seems complex, and it is unknown the extent to which both diseases can manifest independently of each other. However, it is unlikely that all forms of obesity associate with type 2 diabetes or vice versa. It is, therefore, likely that a possible direct link between the two will be limited to a subset of patients.To identify loci influencing obesity in relation to diabetes, a quantitative trait loci (QTL) 1 analysis of BMI was

A genome scan was performed in obese type 2 diabetes mellitus pedigrees to identify susceptibility loci involved in obesity-driven type 2 diabetes mellitus. We studied the 20% most obese diabetes pedigrees from a confined Dutch population from around the town of Breda. Previously we, and others, have already shown that a susceptibility locus influencing obesity in diabetes may reside on chromosome 18p11. We now report evidence to also suggest linkage for type 2 diabetes in these obese pedigrees on chromosome regions 11p (genome-wide P -value ≤ 0·061) and 12q (genome-wide P -value ≤ 0·029), thereby confirming previous findings from corresponding regions. The linkage found in the Breda Cohort of type 2 diabetes patients is influenced by obesity. This supports the notion that a genetic predisposition to obesity is probably intertwined with a genetic predisposition to type 2 diabetes. Further efforts should address the question of how, on a genetic level, these two factors interact.

Previous studies conducted during the COVID-19 pandemic found an increased risk of loneliness due to measurements taken by governments to limit social interaction. The current study addresses the relationship between loneliness and both positive and negative mental health in times of the COVID-19 pandemic and the role of psychological flexibility. Data was collected in the Dutch general population (18+) with two online questionnaires (T1-T2), with an interval of four weeks. A sample of 340 participants varying in age from 18 to 83 years (Mage(SD): 52.83 (13) and 61.8% female, filled in both questionnaires. Loneliness and (the six core processes of) psychological flexibility were measured at T1 and negative mental health (depression, anxiety and stress) and positive mental health (psychological, emotional and social well-being) at T2. Regression analyses indicated a positive prospective relation between loneliness and negative mental health and a negative prospective relation between loneliness and well-being. Psychological flexibility had a moderating effect on the relation between loneliness and negative mental health but not on the relation between loneliness and well-being. Looking at the six core processes of psychological flexibility, only acceptance was a significant moderator of the relation between negative mental health and loneliness.We conclude that while it has yet to be determined whether the moderating relationships found in this study hold beyond COVID-19 conditions, the findings do provide support for the benefits of psychological flexibility to intervene in situations where external circumstances or psychological challenges are beyond one's control.