Risk In First-degree Relatives Research Articles

BR 07-2 THE LINKING IN THE HUMAN (OBSERVATIONAL AND CLINICAL STUDY)

A number of chronic disease conditions tend to cluster in families with an increased risk in first-degree relatives, but also an increased risk in second-degree relatives. This fact is most often referred to as the heritability (heredity) of these diseases and explained by the influence of genetic factors, or shared environment, even if the more specific details or mechanism leading to disease are not known. New methods have to be explored in screening studies and register linkage studies to define and measure consequences of a positive family history of disease. Furthermore, recent studies have indicated that different genetic scores of well-known genetic markers of disease conditions such as obesity, type 2 diabetes or myocardial infarction are only able to explain a minor proportion of this described heritability. Thus, there is still a lack of knowledge to explain the so called “missing heritability” of these disorders [1]. Of particular interest in this perspective is to determine the role of the microbiome, measured as microbiota (the gut bacteria composition and variety, but also from the oral cavity), and its association with dietary intake together with the genetic profile of the host, in relation to alterations in metabolism and immunological function. For example, changes in microbiota composition has been associated with risk of obesity, type 2 diabetes and immunological disturbances as well as with chronic inflammation. This research is linked to other research areas in microbiology, nutritional sciences, technology and innovation for prevention. For example, functional food products can be developed and tailored to match the profile and needs of the individual. Of special interest in a family perspective is that the microbiome of individuals is influenced in early life, in the first place by the microbiota of the mother from exposure to the offspring during delivery and neonatal period. Later on this is influenced by more or less shared microbiota patterns in the household during childhood and adolescence due to cohabitation. It is hypothesized that microbiota profile as well as dietary intake patterns may cluster within families. Recently it was discovered that there is also a specific serum biomarker, the pro-atherosclerotic metabolite, trimethylamine-N-oxide (TMAO) that is able to reflect the gut microbiome and predict cardiovascular events [2]. TMAO can also predict prognosis in patients with congestive heart failure. Interventions to change the microbiota have provided promising results [3] and been described as a potential treatment target for cardio-metabolic disease. Such interventions should be based on the wider use of designed and tested functional food products as part of a healthy lifestyle in general. New findings hypertensive experimental animals and in human patients has revealed a special pattern of different microbiota patterns (dysbiosis) that differs from normotensive controls [4]. This could be linked to early life influences of other factors related to lifestyle in adult life. One idea is to test the influence of antibiotic treatment in these hypertensive individuals to see if vascular function can be improved and blood pressure lowered. We have to learn more about the gastrointestinal tract as potential initial organ of metabolic hypertension, as recently suggested [5]. In summary, the family clustering of cardiometabolic disorders is a well-known clinical observation, but still not fully understood. Genetic factors, even put together in a risk score, can explain just a minor proportion of the increased family risk. New discoveries linking gut microbiota to obesity and cardiometabolic risk conditions, including hypertension, could explain some of this increased clustering. Gut microbiota could potentially be influenced by functional food products and healthy lifestyle, providing a link to cardiovascular and metabolic prevention.

Targeted Echocardiographic Screening for Latent Rheumatic Heart Disease in Northern Uganda: Evaluating Familial Risk Following Identification of an Index Case.

BackgroundEchocardiographic screening for detection of latent RHD has shown potential as a strategy to decrease the burden of disease. However, further research is needed to determine optimal implementation strategies. RHD results from a complex interplay between environment and host susceptibility. Family members share both and relatives of children with latent RHD may represent a high-risk group. The objective of this study was to use echocardiographic family screening to determine the relative risk of RHD among first-degree relatives of children with latent RHD compared to the risk in first-degree relatives of healthy peers.Methodology/Principal FindingsPrevious school-based screening data were used to identify RHD positive children and RHD negative peers. All first-degree relatives ≥ 5 years were invited for echocardiography screening (2012 World Heart Federation Criteria). Sixty RHD positive cases (30 borderline/30 definite RHD) and 67 RHD negative cases were recruited. A total of 455/667 (68%) family members were screened. Definite RHD was more common in childhood siblings of RHD positive compared to RHD negative (p = 0.05). Children with any RHD were 4.5 times as likely to have a sibling with definite RHD, a risk that increased to 5.6 times when considering only cases with definite RHD. Mothers of RHD positive and RHD negative cases had an unexpectedly high rate of latent RHD (9.3%).Conclusions/SignificanceSiblings of RHD positive cases with RHD are more likely to have definite RHD and the relative risk is highest if the index case has definite RHD. Future screening programs should consider implementation of sibling screening following detection of an RHD positive child. Larger screening studies of adults are needed, as data on prevalence of latent RHD outside of childhood are sparse. Future studies should prioritize implementation research to answer questions of how RHD screening can best be integrated into existing healthcare structures, ensuring practical and sustainable screening programs.

Risk of Autoimmunity in EoE and Families: A Population-Based Cohort Study.

Recent genome-wide association studies have suggested possible genetic associations between eosinophilic esophagitis (EoE) and genes associated with autoimmunity. No studies to date have looked at potential genetic association of EoE with specific autoimmune diseases by evaluating such diagnoses within family members. Investigate the risk of specific autoimmune disease within EoE probands and their extended family members. The Utah Population Database offers a unique opportunity to link medical records from over 85% of Utah's population to genealogy records representing Utah. We searched for associations of specific autoimmune diseases in probands diagnosed with EoE and their extended family members (e.g., first cousins). Comparisons were made to age- and sex-matched controls and their respective families at a 5:1 ratio. Excess risk for multiple autoimmune conditions was detected in subjects with a diagnosis of EoE. Celiac, Crohn's, ulcerative colitis (UC), rheumatoid arthritis, IgA deficiency, CVID, multiple sclerosis (MS), and Hashimoto's thyroiditis were found at increased risk in first-degree relatives of EoE subjects. UC, systemic sclerosis, and MS had nominally significant associations within second-degree family members of EoE subjects; and, in reverse analysis, probands and their families with the above three conditions were at an increased risk for EoE suggesting shared genetic factors with EoE. Patients with EoE have an increased risk of multiple autoimmune diseases. Possible shared genetic etiologies were observed between EoE and UC, systemic sclerosis, and MS. Practitioners should be aware of these comorbid associations and query all EoE patients and family members for symptoms of these diseases.

Association of waist and hip circumference and waist-hip ratio with type 2 diabetes risk in first-degree relatives

AimsTo evaluate the association of type 2 diabetes risk in first-degree relatives of diabetics with waist and hip circumference (WC and HC) and waist-hip ratio (WHR). MethodsWe retrieved the data of 1319 subjects who had at least two visits during 2003–2010 and had been examined for diabetes status, WC and HC. Joint survival-longitudinal analysis and Cox regression were performed and the results were compared. ResultsThere was a significant direct relationship between diabetes risk and WC and WHR. The risk increased by 23% (95% CI: 5%–38%) and by 28% (95% CI: 9%–58%) respectively, for every 10cm increase in WC and 10% increase in WHR. Post-hoc subgroup analysis showed that these findings were present in females, but not in males. No significant association was seen for HC. Simple Cox regression showed direct association with WC and HC and no association with WHR. ConclusionsIn addition to dependence on measurement time, results from Cox model were inconclusive. The joint model showed a direct effect of WC and WHR albeit weaker than those in the general population, suggesting the possibility that factors other than the obesity indices are playing a stronger role in the elevated risk in this population. Multivariate models are needed for shedding light on the association.

Alopecia Areata: The Role of Stressful Events and an Estimate of Lifetime Risk in First-Degree Relatives

Background: Alopecia areata (AA) is a common disease in the military population; however, a few studies have calculated the lifetime risk of alopecia areata in first-degree relatives of patients as well as the impact of stress. Objectives: The primary aim of this study was to calculate the lifetime risk of alopecia areata in first-degree relatives of index patients. The secondary aim of this study was to assess the role of stressful events in the onset/recurrence of disease. Patients and Methods: One hundred and twenty-one patients with alopecia areata and their first-degree relatives, which included 597 subjects in addition to 119 controls, were studied. We considered a gender and age-matched control for each patient. They were investigated for the occurrence of stressful events within the previous six months before the onset/recurrence of the disease. Results: More than twenty-six percent of patients had a positive family history, while 6.4 percent of first-degree relatives were affected by alopecia areata. Lifetime risks were estimated at 7.6% for parents, 9.9% for siblings, and 6.4% for children. Eighty-eight patients (73.9%) experienced stressful events within six months prior to the onset or recurrences of alopecia areata, while 32 subjects (26.9%) of the control group reported such events in the last six months (P value = 0.000). Conclusions: Calculated lifetime risks can be used in genetic counseling. It appears that stressful events can be considered to be contributing factors in the development of alopecia areata. Also, according to our results, the role of stress in the recurrence of alopecia areata is more prominent than the primary development of the disease.

Cardiovascular disease risk in first-degree relatives of women with polycystic ovary syndrome

To assess the risk of cardiovascular disease (CVD) in the parents of polycystic ovary syndrome (PCOS) patients using carotid intima medial thickness (CIMT) and brachial artery flow-mediated dilatation (FMD). Hospital-based case-control study. Endocrine clinic of a medical institute in India. Case group of 41 fathers and 45 mothers of PCOS patients (confirmed by Rotterdam's criteria) compared with 42 men and 44 women matched by age, sex and body mass index (BMI) as controls. CVD risk in parents of PCOS patients assessed via CIMT and FMD then correlated with various clinical and metabolic parameters. Differences in CIMT and FMD between parents and controls. The CIMT was higher [0.6 (0.54-0.8) vs. 0.5 (0.45-0.55) mm] and brachial artery FMD was lower [11.9% (6.9%-16.2%) vs. 16.7% (13.5%-22.6%)] in the parents of PCOS patients as compared with the controls. Systolic blood pressure, diastolic blood pressure, low-density lipoprotein cholesterol, and fasting and 2-hour plasma glucose were higher in the parents of the PCOS patients. The prevalence of CVD risk factors such as systemic hypertension, diabetes mellitus, abdominal obesity, the metabolic syndrome, and a family history of coronary artery disease in first-degree relatives was also higher in the parents of PCOS patients. The prevalence of diabetes was higher in the fathers of PCOS women, but other cardiovascular disease risk factors, CIMT, and FMD were comparable among the mothers. The parents of PCOS patients have an increased CVD risk as evidenced by increased CIMT and low FMD.

Cardiovascular risk is linked to body mass index in first-degree relatives of type 2 diabetics

Although cardiovascular (CV) risks are reported in first-degree relatives (FDR) of type 2 diabetics, the pathophysiological mechanisms contributing to these risks are not known. We investigated the association of CV risks with body mass index (BMI) in these subjects. BMI, basal heart rate (BHR), blood pressure (BP), and rate-pressure product (RPP) were measured and analyzed in age-matched subjects of study group (FDR of type 2 diabetics, n = 58) and control group (subjects with no family history of diabetes, n = 92). BMI, BP, BHR, and RPP were significantly increased ( P P = 0.009) of BMI to increased RPP, the marker of CV risk, in the study group, but not in the control group. CV risk in FDR of type 2 diabetics is linked to BMI.

Familial Risks of Tourette Syndrome and Chronic Tic Disorders. A Population-Based Cohort Study.

Tic disorders, including Tourette syndrome (TS) and chronic tic disorders (CTDs), are assumed to be strongly familial and heritable. Although gene-searching efforts are well under way, precise estimates of familial risk and heritability are lacking. Previous controlled family studies were small and typically conducted within specialist clinics, resulting in potential ascertainment biases. They were also underpowered to disentangle genetic from environmental factors that contribute to the observed familiality. Twin studies have been either very small or based on parent-reported tics in population-based (nonclinical) twin samples. To provide unbiased estimates of familial risk and heritability of tic disorders at the population level. In this population cohort, multigenerational family study, we used a validated algorithm to identify 4826 individuals diagnosed as having TS or CTDs (76.2% male) in the Swedish National Patient Register from January 1, 1969, through December 31, 2009. We studied risks for TS or CTDs in all biological relatives of probands compared with relatives of unaffected individuals (matched on a 1:10 ratio) from the general population. Structural equation modeling was used to estimate the heritability of tic disorders. The risk for tic disorders among relatives of probands with tic disorders increased proportionally to the degree of genetic relatedness. The risks for first-degree relatives (odds ratio [OR], 18.69; 95% CI, 14.53-24.05) were significantly higher than for second-degree relatives (OR, 4.58; 95% CI, 3.22-6.52) and third-degree relatives (OR, 3.07; 95% CI, 2.08-4.51). First-degree relatives at similar genetic distances (eg, parents, siblings, and offspring) had similar risks for tic disorders despite different degrees of shared environment. The risks for full siblings (50% genetic similarity; OR, 17.68; 95% CI, 12.90-24.23) were significantly higher than those for maternal half siblings (25% genetic similarity; OR, 4.41; 95% CI, 2.24-8.67) despite similar environmental exposures. The heritability of tic disorders was estimated to be 0.77 (95% CI, 0.70-0.85). There were no differences in familial risk or heritability between male and female patients. Tic disorders, including TS and CTDs, cluster in families primarily because of genetic factors and appear to be among the most heritable neuropsychiatric conditions.

Su1950 Increased Colorectal Cancer Risk in First-Degree Relatives of Patients With Multiple Serrated Polyps Who Do Not Fulfill Criteria for Serrated Polyposis Syndrome

in 32 (15.4%) AJ and 22 (0.5%) NAJ (p=0.0001); among AJ this variant was significantly associated with a diagnosis of CRC (OR: 2.6 [95% CI: 1.1-5.8]). Conclusion: Overall, the frequency of pathogenic APC or MUTYH mutations increases with adenoma count and is lower in AJ compared to NAJ. The low yield of comprehensive MUTYH testing in AJ suggests this gene plays a small role in AJ with polyposis and that other genes may be responsible for the polyposis phenotype in Ashkenazim. The higher prevalence of the APC*R332X mutation in AJ compared to NAJ suggests R332X may be a founder mutation. This should be further explored through haplotype analysis. Finally, we propose that increased colorectal screening be considered in Ashkenazim who have the I1307K variant and report a personal history of colorectal adenomas.

Population-based, multi-generational family clustering study of social anxiety disorder and avoidant personality disorder.

We aimed to provide unbiased estimates of familial risk and heritability of social anxiety disorder (SAD) and avoidant personality disorder (AVPD). We identified 18 399 individuals diagnosed with SAD and 2673 with AVPD in the Swedish National Patient Register between 1997 and 2009. Risks (odds ratios; OR) for SAD in all biological and non-biological relatives of probands, compared to relatives of unaffected individuals were calculated. We also estimated the risks for AVPD in relatives of probands with SAD. The risk for SAD among relatives of SAD probands increased proportionally to the degree of genetic relatedness. The risks for first-degree relatives [OR 4.74, 95% confidence interval (CI) 4.28-5.25] were significantly higher than for second-degree and third-degree relatives. Second-degree relatives (OR 2.30, 95% CI 2.01-2.63) had significantly higher risk than third-degree relatives (OR 1.72, 95% CI 1.52-1.94). Relatives at similar genetic distances had similar risks for SAD, despite different degrees of shared environment. Heritability was estimated to be approximately 56%. There were no significant sex differences in the familial patterns. The risk of AVPD in relatives of SAD probands was significantly elevated, even after excluding individuals with both diagnoses (first-degree OR 3.54, second-degree OR 2.20, third-degree OR 1.62). Non-biological relatives (spouses/partners) also had elevated risks for both SAD (OR 4.01) and AVPD (OR 3.85). SAD clusters in families primarily due to genetic factors. SAD and AVPD are aetiologically related and may represent different expressions of the same vulnerability. The strong marital concordance observed in SAD/AVPD may indicate assortative mating but the exact mechanisms and implications require further investigation.

Prevalence of Psychiatric Disorders in First-degree Relatives of Patients With Drug Dependence With and Without Comorbid Psychiatric Disorder Using the Family History Method (FH-RDC)

Aim: The aim of this study was to evaluate psychiatric morbidity risks in first-degree relatives of patients with drug dependence with and without comorbid psychiatric disorder. Methods: The case-control study was carried out in Nigeria. The Family History Method was used to evaluate psychiatric disorders in the first-degree relatives of the patients. Results: The family psychiatric morbidity risks did not predict the development of comorbid psychiatric disorder among the probands. However, psychiatric disorder in the probands correlated significantly with cannabis use, more so with early age at onset of its use. Conclusions: Familial psychiatric morbidity risk was not associated with psychiatric disorder in patients with drug dependence.

First-degree relative risk: in utero levetiracetam and valproate exposure.

First-degree relative risk: in utero levetiracetam and valproate exposure.

The Association Between Schizophrenia and Rheumatoid Arthritis: A Nationwide Population-Based Swedish Study on Intraindividual and Familial Risks

Numerous studies have reported a reduced risk of rheumatoid arthritis (RA) in schizophrenia. The mechanisms are unknown, but recent genome-wide association studies of schizophrenia have shown strong associations with markers spanning the major histocompatibility complex region, indicating a possible role for adaptive immunity also in schizophrenia. In this population-based cohort study, we assess the associations between RA and schizophrenia and the extent to which any observed associations are specific to RA/schizophrenia. We then extend the assessments per RA subtype and to risks in first-degree relatives. The study population included every individual identified in the Swedish Population Register born in Sweden between 1932 and 1989. The risk for RA in schizophrenia was significantly decreased (hazard ratio [HR] = 0.69, 95% CI = 0.59-0.80), but similar reductions were noted for osteoarthritis (a noninflammatory joint disorder) and ankylosing spondylitis (a non-RA inflammatory disorder). Comparable associations were seen in schizoaffective subjects while no significant associations were observed in bipolar disorder. Overall, first-degree relatives of schizophrenia patients were not at reduced risk of RA, but the risk for seronegative RA was significantly decreased in children and siblings of schizophrenia probands (HR = 0.13, 95% CI = 0.02-0.95 and HR = 0.67, 95% CI = 049-0.92, respectively). In conclusion, our intraindividual analyses suggest that differential misclassification bias is an important factor for the observed inverse association and emphasize the need of optimized care-provision for nonpsychiatric symptoms in schizophrenia patients. Our familial analyses indicted the possibility of an inverse coinheritance of schizophrenia and seronegative RA.

Risk of congenital heart disease in relatives of probands with conotruncal cardiac defects: An evaluation of 1,620 families

Current recurrence risk counseling for conotruncal cardiac defects (CTD) is based on empiric estimates from multiple studies. We examined the risk of congenital heart disease (CHD) in relatives of probands with CTDs to assist in counseling practices in the current era. One thousand six-twenty probands with CTDs and no reported chromosomal or genetic abnormalities were recruited sequentially. A three-generation pedigree was obtained for each proband by a genetic counselor detailing the presence and type of CHD in each family member. Risks and 95% confidence intervals (CI) were calculated for sub-groups of relatives based on degree of relationship for all probands and by individual lesion of the proband. For pairs of affected relatives, concordance rates were calculated. Severity of CHD in the affected relative was assessed. The risk of CHD was higher in siblings (4.4%, 95% CI 3.4-5.4) than in parents (1.5%, 95% CI 1.1-1.9). Risk varied by the cardiac lesion of the proband with the highest risk in first-degree relatives of probands with tetralogy of Fallot and the lowest in D-transposition of the great arteries. 39% of affected parents and 69% of affected siblings had a concordant lesion (i.e., CTD). Most affected siblings of probands with severe CTDs had complex defects (58%), whereas very few affected parents had complex defects (20%). These data suggest that recurrence risk varies by lesion and relationship, with substantial concordance observed by cardiac lesion and complexity of disease, particularly among siblings. These findings contribute to risk counseling in the current era.

Association of hypertension status and cardiovascular risks with sympathovagal imbalance in first degree relatives of type 2 diabetics.

As reports show cardiovascular (CV) risks in first-degree relatives (FDR) of type2 diabetics, and autonomic imbalance predisposing to CV risks, in the present study we have assessed the contribution of sympathovagal imbalance (SVI) to CV risks in these subjects. Body mass index (BMI), waist-to-hip ratio (WHR), basal heart rate (BHR), blood pressure (BP), rate pressure product (RPP), and spectral indices of heart rate variability (HRV) were reordered and analyzed in FDR of type2 diabetics (study group, n=293) and in subjects with no family history of diabetes (control group, n=405). The ratio of low-frequency (LF) to high-frequency (HF) power of HRV (LF-HF), a sensitive marker of SVI, was significantly increased (P<0.001) in the study group compared with the control group. The SVI in the study group was due to concomitant sympathetic activation (increased LF) and vagal inhibition (decreased HF). In the study group, the LF-HF ratio was significantly correlated with BMI, WHR, BHR, BP and RPP. Multiple regression analysis showed an independent contribution of LF-HF to hypertension status (P=0.000), and bivariate logistic regression showed significant prediction (odds ratio 2.16, confidence interval 1.130-5.115) of LF-HF to increased RPP, the marker of CV risk, in the study group. Sympathovagal imbalance in the form of increased sympathetic and decreased parasympathetic activity is present in FDR of type2 diabetics. Increased resting heart rate, elevated hypertension status, decreased HRV and increased RPP in these subjects make them vulnerable to CV risks. SVI in these subjects contributes to CV risks independent of the degree of adiposity.

Effects of Gender on Sympathovagal Imbalance, Prehypertension Status, and Cardiovascular Risks in First-Degree Relatives of Type 2 Diabetics

Although cardiovascular (CV) risks are reported in first-degree relatives (FDRs) of type 2 diabetics, effects of gender on sympathovagal imbalance (SVI) and CV risks in these subjects have not been investigated. Body mass index (BMI), blood pressure variability parameters including baroreflex sensitivity (BRS), spectral indices of heart rate variability, autonomic function tests, insulin resistance, lipid profile, inflammatory markers (interleukin 6, high-sensitivity C-reactive protein, tumor necrosis factor α) and oxidative stress (OS) marker were measured and analyzed in control group (without family history of diabetes; 65 women, 60 men) and study group (FDRs of type 2 diabetics; 52 women, 49 men) subjects. BMI, heart rate, blood pressure, rate-pressure product, stroke volume, left-ventricular ejection time, cardiac output, total peripheral resistance, homeostatic model of insulin resistance, lipid profile, inflammatory and OS markers, and ratio of low-frequency to high-frequency power of heart rate variability (LF-HF ratio), a sensitive marker of SVI, were significantly increased, and BRS was significantly decreased in study group men compared with women. SVI was more intense in men and was due to concomitant sympathetic activation and vagal inhibition. There was no SVI in control subjects. Multiple regression analysis demonstrated independent contribution of BMI, homeostatic model of insulin resistance, atherogenic index, inflammatory and OS markers, and BRS to LF-HF ratio. Logistic regression analysis demonstrated significant prediction of prehypertension status and rate-pressure product (markers of CV risk) by LF-HF, which was more prominent in men. SVI is more intense in male FDRs of type 2 diabetics, and SVI is associated with increased CV risk due to insulin resistance, dyslipidemia, inflammation, and oxidative stress in these subjects.

Familial aggregation of cluster headache

Several studies suggest a strong familial aggregation for cluster headache (CH), but so far none of them have included subjects with probable cluster headache (PCH) in accordance with the International Classification of Headache Disorders. To identify cases of probable cluster headache and to assess the familial aggregation of cluster headache by including these subjects. Thirty-six patients attending a headache consultation and diagnosed with trigeminal autonomic headaches were subjected to a questionnaire-based interview. A telephone interview was also applied to all the relatives who were pointed out as possibly affected as well as to some of the remaining relatives. Twenty-four probands fulfilled the criteria for CH or PCH; they had 142 first-degree relatives, of whom five were found to have CH or PCH, including one case of CH sine headache. The risk for first-degree relatives was observed to be increased by 35- to 46-fold. Our results suggest a familial aggregation of cluster headache in the Portuguese population.

The FOXE1 locus is a major genetic determinant for familial nonmedullary thyroid carcinoma

Thyroid cancer is the most common endocrine malignancy and nonmedullary thyroid carcinoma (NMTC) represents 90% of all cases. NMTC risk in first-degree relatives of affected cases is elevated fivefold to ninefold. Familial NMTC (FNMTC) accounts for about 3-7% of all thyroid tumors and is a more aggressive clinical entity than its sporadic counterparts. Linkage analysis on high-risk families performed a decade ago mapped several susceptibility loci, but did not lead to the identification of high-penetrance causal germline mutations. More recently, a genome-wide association study (GWAS) identified common single nucleotide polymorphisms (SNPs) affecting the risk of sporadic NMTC. We sought to verify if the newly identified genetic risk factors for NMTC are relevant for FNMTC as well. We genotyped 23 SNPs at 11 candidate loci in 672 subjects belonging to 133 pedigrees with at least two NMTC cases. Statistical analysis was performed using family-based association tests, modified quasi-likelihood score and logistic-normal models. SNPs at 9q22.33 near FOXE1 showed convincing evidence of association with NMTC risk in these high-risk families. The other tested loci resulted negative. These findings confirm the importance of the SNPs identified by recent GWAS on sporadic NMTC on FNMTC as well. However, the proposed FOXE1 causal variants do not show the strongest association signal. Moreover, mutation screening of the FOXE1 coding sequence in the FNMTC cases did not identify rarer causal variants, suggesting that other yet unidentified variants at this locus are involved in FNMTC etiology.

Population-Based, Multigenerational Family Clustering Study of Obsessive-compulsive Disorder

Controlled family studies have consistently found that obsessive-compulsive disorder (OCD) aggregates in families but have typically relied on samples recruited from specialist clinics. Furthermore, previous studies could not disentangle genetic from environmental factors contributing to the observed familiality. To provide unbiased estimates of familial risk for and heritability of OCD at the population level. Population-based, multigenerational, case-control family and twin studies using the Swedish National Patient Register, Multi-Generation Register, and Twin Register. All individuals diagnosed as having OCD between January 1, 1969, and December 31, 2009 (n = 24 768) and all their available first-, second-, and third-degree relatives, as well as nonbiological relatives and matched general population control subjects. Twins (n = 16 383) were included from the population-based Twin Register. The risk for OCD among relatives of OCD probands. The risk for OCD among relatives of OCD probands increased proportionally to the degree of genetic relatedness. The risk for first-degree relatives was significantly higher than that for second- and third-degree and nonbiological relatives. Second-degree relatives had higher risk for OCD than third-degree relatives. Relatives at similar genetic distances had similar risks for OCD, despite different degrees of shared environment. Separate twin modeling analyses confirmed that familial risk for OCD was largely attributable to additive genetic factors (47%; 95% CI, 42%-52%), with no significant effect of shared environment. Nonbiological relatives (spouses or partners who have at least 1 child together) also had an elevated risk for OCD (odds ratio, 2.61; 95% CI, 1.99-3.42). Early-onset probands (3907 individuals; mean age, 13.7 years) had slightly (nonsignificantly) higher familial risk than the total sample, although this was substantially lower than previously reported. There were no significant sex differences in the familial pattern or heritability estimates. Obsessive-compulsive disorder clusters in families primarily due to genetic factors. Nonshared environmental factors are at least as important. The quest for candidate genes, nonshared environmental risk factors, and their possible correlation or interaction should continue. The finding of possible assortative mating in OCD is intriguing and should be investigated further.

AB0017 Association study of genetic risk variants for psoriasis in a large cohort of psoriatic arthritis, psoriasis and controls of the spanish population and association with relevant clinical subphenotypes

BackgroundPsoriatic Arthritis (PsA) is a complex disease with a substantial genetic risk component (first-degree relative risk ∼55). Recently, Genomewide Association Studies (GWAS) have expanded the number of risk loci for...