Sibling Risk Research Articles

Sibling risk of anxiety disorders based on hospitalizations in Sweden

This study used nationwide hospital records to examine sibling risk of any type of anxiety disorder in Sweden over a 40-year period. This study, carried out between 1 January 1968 and 31 December 2007, of the entire population of Sweden, linked information on family relationships from the nationwide Multi-Generation Register with information from the nationwide Swedish Hospital Discharge Register on first diagnosis of anxiety disorder. A total of 42,602 persons hospitalized for anxiety disorders and 2093 affected siblings were identified. Standardized incidence ratios (SIR) were calculated by comparing risk in siblings of persons hospitalized for anxiety disorders with risk in persons whose siblings had no hospital diagnosis of anxiety disorders. The sibling risk was 2.26, which was independent of sex and age differences between siblings. The SIR was highest in siblings <20 years of age (2.83). Analysis of risk by subtype showed that having a sibling diagnosed with any anxiety disorder resulted in increased risks of a number of disorders; the highest increased risk was of social phobia (SIR 3.68, 95% confidence interval, 1.68-7.69). Risk of panic disorder, generalized anxiety disorder, mixed anxiety and depressive disorder, and obsessive-compulsive disorder was raised in female but not male siblings. Heritable effects likely play an important role in the cause of anxiety disorders, but the extent of their role remains to be established. Important contributions could be made by studies of gene-environment interactions that have sufficient sample sizes to produce reliable results.

Genetic Assessment of Cortical Malformations

Malformations of cortical development comprise a clinically and etiologically heterogeneous group of distinct structural abnormalities of the cerebral cortex, commonly identified during MR imaging of patients with seizure disorders and/or developmental delay. MR imaging is crucial for further classification and together with additional clinical information and family history guiding specific genetic testing, which today is an integral part of the interdisciplinary diagnostic work-up and allows identification of an underlying genetic alteration in a significant subset of patients. Results of genetic testing may provide important prognostic information and subsequently support prospective therapeutic decisions. Furthermore, genetic forms of cortical malformations may be associated with a significantly increased recurrence risk for further siblings or other relatives and require genetic counselling of the family on individual risks and the options of prenatal or even preimplantation genetic diagnosis.

Anophthalmos, Microphthalmos, and Typical Coloboma in the United Kingdom: A Prospective Study of Incidence and Risk

Anophthalmos, microphthalmos, and typical coloboma (AMC) form an interrelated spectrum of congenital eye anomalies that can cause significant visual loss and cosmetic disfigurement in children. This prospective study of children born in the United Kingdom was undertaken to determine the incidence of AMC diagnosed by ophthalmologists and to explore sociodemographic risks. Recruitment was achieved though an established active surveillance system of U.K. ophthalmologists supported by a new research network of interested specialists, the Surveillance of Eye Anomalies (SEA-UK) Special Interest Group. It started October 1, 2006, and continued over 18 months. One hundred thirty-five children were newly diagnosed with AMC. Typical colobomatous defects were the commonest phenotype, and anophthalmos was rare (n = 7). Both eyes were affected in 55.5% of the children. The cumulative incidence of AMC by age 16 years was 11.9 per 100,000 (95% CI, 10.9-15.4). Of the children examined, 41.5% had not seen an ophthalmologist by 3 months of age. The incidence in Scotland was nearly double that in England and Wales. The children of Pakistani ethnicity had a 3.7 (95% CI, 1.9-7.5) times higher risk of AMC than did white children. There was some evidence to suggest a higher incidence in the more socioeconomically deprived. The sibling risk ratio was 210 (95% CI, 25-722). This is the first prospective study of AMC, and it establishes the frequency across the United Kingdom. Comparisons with data quoted in the literature are difficult because study methodologies differ, but the frequency appears to be lower than that quoted for other developed countries. There are geographic and ethnic variations in incidence that warrant further investigation.

The Heritability and Sibling Risk of Angle Closure in Asians

To describe the heritability and sibling risk for angle closure. Prospective clinical study. Probands with primary angle closure (PAC) and primary angle-closure glaucoma (PACG) and their first-degree relatives. One hundred probands with PAC and PACG and their first-degree relatives were examined prospectively. All subjects underwent an ophthalmic evaluation that included slit-lamp examination, optic disc evaluation, and gonioscopy. An angle was classified as narrow if the posterior (usually pigmented) trabecular meshwork could be seen for less than 180° of the angle circumference. The heritability of narrow angles was calculated by threshold models. The sibling recurrence and relative risk of having narrow angles compared with the general population was calculated using estimation of sibling genetic risk parameters, corrected for single ascertainment bias. Heritability and sibling risk for narrow angles. One hundred probands (consisting of 76 subjects with PACG and 24 with PAC) were examined together with 327 first-degree relatives. There were 76 female probands and 24 male probands. Of the first-degree relatives, 146 were male and 181 were female. Of the 327 first-degree relatives, 105 (32.1%) had narrow angles. The heritability of narrow angles was 58.8% overall, with the genetic variance being 2.30 and the phenotypic variance being 3.91. Of the 515 sibling pairs examined, 171 (33.1%) pairs had both siblings unaffected, 113 (21.9%) pairs had both siblings affected, 231 (45.0%) pairs had 1 sibling affected. The sibling recurrence risk for having narrow angles was 49% (95% confidence interval, 41.6%-56.8%), whereas the sibling relative risk for narrow angles was 7.57 (95% confidence interval, 6.41-8.74). A high heritability of narrow angles of almost 60% was found. Siblings of Chinese patients with PAC or PACG have almost a 50% probability of having narrow angles and are more than 7 times more likely to have narrow angles than the general population.

Development of a Dynamic Simulation Model to Estimate Population Mortality Effects Resulting From the Availability of Smokeless Tobacco Products

S (ACE) AEP Vol. 20, No. 9 September 2010: 691–724 716 P93 DEVELOPMENT OF A DYNAMIC SIMULATION MODEL TO ESTIMATE POPULATION MORTALITY EFFECTS RESULTING FROM THE AVAILABILITY OF SMOKELESS TOBACCO PRODUCTS A Bachand, G Curtin, J Swauger, S Sulsky, Colorado State University, Fort Collins, CO; R J Reynolds Tobacco Co., Winston-Salem, NC; ENVIRON International Corp., Amherst, MA PURPOSE: Potential harm reduction resulting from smokeless tobacco (ST) use has received considerable attention. We are developing a model to estimate changes in future population mortality due to availability of ST that is expected to improve upon previous models. METHODS:We used theWinBUGS computer program to create a simulation that estimates mortality for a hypothetical population of persons who have never used tobacco and who, as they age, may transition into and out of tobacco exposure states, including current and former smoking or ST use. Markov Chain Monte Carlo techniques were used to estimate the variability of the results. All model inputs, including age-specific transition probabilities, are specified by the user. RESULTS: The model allows for 15 possible transitions into and out of tobacco exposure states, tracks individual exposure histories, and estimates ageand exposure-history-specific allcause or cause-specificmortality. At each age and at the end of follow-up, the model estimates the number of survivors under two different assumptions-that ST is either available or unavailable-and calculates the difference between the two results. Estimated deaths under the baseline exposure scenario (no ST) closely approximate recent US mortality based on CDC lifetable data. Some alternative exposure scenarios showed benefits from the introduction of ST. DISCUSSION: The simulation model was developed to use and document any inputs and any defined baseline exposure scenario.We expect models such as this one to be informative for development of harm reduction policies. P71 WITHIN-FAMILY ESTIMATES FOR THE ASSOCIATION BETWEEN SIBLING BIRTH ORDER AND RISK FOR AUTISM K Cheslack-Postava, KY Liu, P Bearman, Robert Wood Johnson Foundation Health & Society Scholars, Columbia University, New York, NY PURPOSE:Birth cohort studies have shown an inverse association between maternal parity and risk for autism, but whether this is due to biological mechanisms, confounding by family-level factors, or “stoppage” is not known. Investigating within-family patterns of association will enable us to differentiate between these alternative explanations. METHODS: Sibships consisting of full sibling singleton births occurring between 1992 and 2002 were identified using California birth records, and autism diagnoses were determined using Department of Developmental Services client files. Conditional logistic regression and multi-level models were used to estimate within-family association between birth order and risk for autism. RESULTS: Second and later born children were at increased risk of autism relative to their first-born siblings. The association between birth order and autism diagnosis was time dependent, such that the increased risk occurred when interval between pregnancies was short (OR and 95% CI for second versus first born siblings Z 2.15 (1.87, 2.47) for a 6 month versus 0.99 (0.87, 1.13) for a 24 month pregnancy interval). CONCLUSION: Within-family effect estimates suggest that risk of autism is increased in non-firstborn children relative to firstborn siblings. The increased risk occurs in closely spaced pregnancies, and may indicate a role for nutritional factors. This is different from the pattern in birth cohort analyses, illustrating the utility of applying different modeling approaches. P72 COMPARING METHODS FOR IMPUTING MISSING HEIGHT AND IMPACT ON BODY MASS INDEX MG DeForest, EC Wong, LP Palaniappan, Palo Alto Medical Foundation Research Institute, Palo Alto, CA PURPOSE: To compare common statistical methods for imputing missing values, as applied to height for the calculation of body mass index (BMI) in clinical settings. METHODS: A sample of 9,824 patients with complete height information (height recorded for every weight recorded) was derived from a clinic in Northern California. Patterns of missing heights were simulated for each patient in this sample based on data from other clinic patients who were matched on sex, age, race/ethnicity, and number of clinic visits. Five common imputation methods for missing patient height were compared: patient-specific mean height, median height, mode height, last observed height carried forward (LOCF) and last observed height carried forward then backward (LOCFB). The proportion of imputable height values, and the patient-specific mean squared error (MSE; mean, standard error) for BMI was compared across the five methods. RESULTS: The proportion of imputable values ranged from 16% for mode height, to 100% for mean height, median height, and LOCFB. The MSE of BMI for each method was mean height (meanZ0.48, seZ0.05), median height (0.47, 0.05), mode height (0.29, 0.08), LOCF (0.55, 0.06), LOCFB (0.50, 0.05).

Within-Family Estimates for the Association Between Sibling Birth Order and Risk for Autism

Within-Family Estimates for the Association Between Sibling Birth Order and Risk for Autism

Sibling caregiving among children orphaned by AIDS: Synthesis of recent studies for policy implications

The HIV/AIDS epidemic has increased the number of orphans who have to care for their younger siblings. However, their caregiving practices are poorly reported. This review aimed to explore and accumulate available evidences on sibling caregiving among children orphaned by AIDS. We conducted a systematic review of sibling caregiving among AIDS orphans in developing countries and identified 25 relevant articles. We analysed the compiled literature and extracted information on the prevalence of sibling caregiving, the framework of sibling caregiving, factors influencing caregiving, and the impact of sibling caregiving on caregivers and those cared for. Sibling caregiving, which includes economic, physical, psychological, and educational care, was influenced by children's, familial, community, and policy factors. Unlike sibling caregiving that occurs under adequate adult supervision, sibling caregiving among AIDS orphans negatively impacts both the sibling caregivers and the cared for. However, the lack of studies about such sibling caregiving had prevented measurement of the level of burden and impact of sibling caregiving on orphans. Policy makers need to be aware that older children caring for younger siblings risk physical and psychological ill health and information must be collected so that measures can be developed to mitigate this burden on orphans.

Evolutionary and Functional Analysis of Celiac Risk Loci Reveals SH2B3 as a Protective Factor against Bacterial Infection

Celiac disease (CD) is an intolerance to dietary proteins of wheat, barley, and rye. CD may have substantial morbidity, yet it is quite common with a prevalence of 1%-2% in Western populations. It is not clear why the CD phenotype is so prevalent despite its negative effects on human health, especially because appropriate treatment in the form of a gluten-free diet has only been available since the 1950s, when dietary gluten was discovered to be the triggering factor. The high prevalence of CD might suggest that genes underlying this disease may have been favored by the process of natural selection. We assessed signatures of selection for ten confirmed CD-associated loci in several genome-wide data sets, comprising 8154 controls from four European populations and 195 individuals from a North African population, by studying haplotype lengths via the integrated haplotype score (iHS) method. Consistent signs of positive selection for CD-associated derived alleles were observed in three loci: IL12A, IL18RAP, and SH2B3. For the SH2B3 risk allele, we also show a difference in allele frequency distribution (Fst) between HapMap phase II populations. Functional investigation of the effect of the SH2B3 genotype in response to lipopolysaccharide and muramyl dipeptide revealed that carriers of the SH2B3 rs3184504*A risk allele showed stronger activation of the NOD2 recognition pathway. This suggests that SH2B3 plays a role in protection against bacteria infection, and it provides a possible explanation for the selective sweep on SH2B3, which occurred sometime between 1200 and 1700 years ago.

Family Study of Restless Legs Syndrome in Quebec, Canada

To fully ascertain the familial aggregation of restless legs syndrome (RLS) and to characterize the clinical features of familial RLS (fRLS) cases. A case series survey with a high response rate. Academic research center. Consecutive RLS probands (n = 249) were followed up in a specialized sleep center for 15 years. A total of 671 cases of fRLS met the current standard diagnostic criteria, including 192 probands characterized using multidimensional clinical assessments and 479 affected family members assessed by their responses to a structured questionnaire telephone diagnostic interview. Sibling and offspring relative risk ratio and clinical and genetic features of patients with fRLS and families. Our data showed that RLS aggregates in families with a familial rate of 77%, a sibling relative risk of 3.6 (95% confidence interval, 2.8-4.4), and an offspring relative risk of 1.8 (1.0-2.7). Familial RLS is a chronic disorder with a mean (SD) disease duration of 24 (16) years and a wide range of age of onset (mean [SD], 28 [15] years), with most family members having early-onset disease but mild to moderate RLS symptoms. Our clinical data also indicated that fRLS is more prominent among women who also had increased incidence of anemia/iron deficiency, arthritis, and number of pregnancies. Pregnancy-related RLS seems to be a characteristic feature of fRLS, and afflicted women tend to have a much younger age of onset. Restless legs syndrome significantly aggregated in families with variable phenotypic expressivity, and the siblings of severely affected individuals have an increased risk of developing the disease.

How an adolescent's childbearing affects siblings' pregnancy risk: a qualitative study of Mexican American youths.

The siblings of teenage parents are known to be at very high risk of teenage pregnancy, but little is known about how an older sister's childbearing affects a younger sibling's risk. Understanding these influences could help address the very high rates of pregnancy and childbearing among Latino adolescents. From 2005 through 2007, a sample of 41 Mexican American 12-18-year-olds from southern California completed in-depth interviews about how an older sister's teenage childbearing had affected them. Themes that emerged were categorized as risk factors (circumstances that increased youths' likelihood of becoming involved in a teenage pregnancy) or protective factors (conditions that reduced this likelihood) on the basis of well-established findings in the literature. Interview data reflected six risk factors and 11 protective factors. The most commonly reported risk factors (discussed by more than a quarter of participants) were that youths did not perceive early parenting as a hardship, had increased difficulties in school and wanted to have a baby too. The most commonly cited protective factors (mentioned by more than half) were an increased motivation to avoid early parenting, an increased appreciation of the difficulties of parenting, mothers' explicitly discouraging early parenting and youths' feeling of greater closeness with their mother. Interventions that build on the protective factors that result when a youth's older sibling has a teenage birth, while reducing the risk factors, might help families prevent younger children from becoming involved in a teenage pregnancy.

Increased Risk of Complex Regional Pain Syndrome in Siblings of Patients?

An increased risk among siblings of probands with complex regional pain syndrome (CRPS) may be indicative of a genetic contribution. We calculated the sibling recurrence risk ratio (lambda(sibling)), a measure of familial aggregation. We surveyed 405 CRPS patients to collect information on the occurrence of CRPS in their siblings and compared this risk with the population risk to develop the syndrome. Information on disease status was collected from 1242 siblings, of which 24 were possibly affected according to their siblings. The diagnosis was confirmed in 16 patients, rejected in 2, and could not be verified in the remaining 6. Age-specific risk ratios were calculated for younger (<50 years) and older (> or =50 years) age groups. The strongest effects were seen in the younger age group, with a lambda(sibling) for possibly affected and confirmed cases of 5.6 (95% CI, 3.0 to 9.8) and 3.4 (95% CI, 1.5 to 6.8), respectively. We concluded that this study yielded no indications for an overall increased risk of developing CRPS for siblings of CRPS patients but that the risk was significantly increased in siblings younger than 50, which may indicate that genetic factors play a more pronounced role in this subgroup. We studied the risk of developing CRPS for siblings of patients with this syndrome. Although the overall risk for siblings was not increased compared with the population risk, the risk for younger siblings was elevated. To enhance chances of success, future genetic studies may consider restricting inclusion to younger-onset cases.

A cohort study of recurrence patterns among more than 54,000 relatives of oral cleft cases in Denmark: support for the multifactorial threshold model of inheritance

Objectives: To determine if the anatomical severity of oral clefting affects familial recurrence in a large population based sample. To provide reliable recurrence risk estimates for oral cleft for first-,...

APC Somatic Mosaicism in a Patient with Gardner Syndrome Carrying the E1573X Mutation: Report of a Case

We report a case of somatic APC mosaicism in an person with a clinical diagnosis of Gardner syndrome with features of attenuated polyposis coli and with an uninformative family history. In initial screening for APC mutations, the germline mutation E1573X was detected in a lower proportion than that predicted by a heterozygous mutation indicating the presence of somatic mosaicism. Pyrosequencing confirmed this hypothesis and quantified the presence of the mutation in approximately 18% of the blood lymphocytes. Mutational analysis performed in the offspring revealed a fully heterozygous E1573X mutation in 2 of the 3 individuals tested. The milder colonic phenotype exhibited by the index patient could be a consequence of the presence of the mosaicism in the colon mucosa. The detection of the mutation in other tissues and in the offspring suggests that it may have occurred early during embryogenesis, before the separation of the embryonic layers. The E1573X mutation is the most distal mutation in the APC sequence reported to date as a mosaic and, interestingly, in the context of Gardner syndrome with extensive extracolonic features. Mosaicism is an important consequence of de novo APC mutations and it should be considered in the management of apparently sporadic or de novo cases, particularly in the evaluation of the risk of siblings and offspring.

Sibling risk of pediatric obstructive sleep apnea syndrome and adenotonsillar hypertrophy.

To estimate sibling risk of hospitalization for children with sleep disordered breathing (SDB), diagnosed with (1) obstructive sleep apnea syndrome (OSAS), or (2) adenotonsillar hypertrophy in the total Swedish population. Using the MigMed database at the Karolinska Institute, we divided the population of Sweden aged 0-18 years into sibling groups based on a shared mother and father and presence of a primary hospital diagnosis of OSAS or adenotonsillar hypertrophy for each individual born between 1978 and 1986, during the follow-up period 1997-2004. Individuals with at least one affected sibling were identified and the incidence rates were computed, using standardized incidence ratios (SIRs) with 95% confidence intervals (CIs). Reference groups were boys and girls with unaffected siblings of 2 or more. After accounting for socioeconomic status, age, and geographic region, boys with at least one sibling with OSAS had an increased risk of having OSAS (SIR, 33.2; 95% CI, 16.5-64.8), and in girls the SIR was 40.5 (19.4-81.4). For hypertrophy of the tonsils or hypertrophy of the adenoids and tonsils the corresponding SIRs were 4.53 (3.0-6.8) for boys and 4.94 (3.3-7.4) for girls. The study indicate an increased sibling risk of sleep disordered breathing in children, which may be due to heritable genes and/or shared environment such as increased awareness among family members or referring doctors. Caregivers should ask parents if siblings have similar symptoms, and thus offer them early treatment.

Schizophrenia patients and their healthy siblings share disruption of white matter integrity in the left prefrontal cortex and the hippocampus but not the anterior cingulate cortex

Healthy siblings of schizophrenia patients have an almost 9-fold higher risk for developing the illness than the general population. Disruption of white matter (WM) integrity as indicated by reduced fractional anisotropy (FA) derived from diffusion tensor imaging (DTI), is believed to be the key substrate of schizophrenia. However, it remains unclear whether schizophrenia patients and their healthy siblings share a specific pattern of disruption of WM integrity that may be related to the disease risk. The objective of this study is to determine whether a specific brain regional pattern of disruption of WM integrity is shared by schizophrenia patients and their healthy siblings. We investigated brain white matter abnormalities by voxel-based analysis of white matter FA data acquired from diffusion tensor imaging in 34 pairs of schizophrenia patients and their healthy siblings, as well as in 32 healthy controls. Both schizophrenia patients and their healthy siblings showed reduced white matter FA in the left prefrontal cortex and the hippocampus in comparison to healthy controls, without significant difference between patients and siblings. In marked contrast, only schizophrenia patients exhibited reduced white matter FA in the left anterior cingulate cortex in comparison to both siblings and controls, without significant difference between siblings and controls. Thus, schizophrenia patients and their healthy siblings share disruption of WM integrity in the left prefrontal cortex and the hippocampus that may be related to higher risk of healthy siblings to develop schizophrenia, which may be eventually attributed to additional disruption of WM integrity in the left anterior cingulate cortex.

Prostate cancer segregation analyses using 4390 families from UK and Australian population‐based studies

Familial aggregation of prostate cancer is likely to be due to multiple susceptibility loci, perhaps acting in conjunction with shared lifestyle risk factors. Models that assume a single mode of inheritance may be unrealistic. We analyzed genetic models of susceptibility to prostate cancer using segregation analysis of occurrence in families ascertained through population-based series totaling 4390 incident cases. We investigated major gene models (dominant, recessive, general, X-linked), polygenic models, and mixed models of susceptibility using the pedigree analysis software MENDEL. The hypergeometric model was used to approximate polygenic inheritance. The best-fitting model for the familial aggregation of prostate cancer was the mixed recessive model. The frequency of the susceptibility allele in the population was estimated to be 0.15 (95% confidence interval (CI) 0.11-0.20), with a relative risk for homozygote carriers of 94 (95% CI 46-192), and a polygenic standard deviation of 2.01 (95% CI 1.72-2.34). These analyses suggest that one or more genes having a strong recessively inherited effect on risk, as well as a number of genes with variants having small multiplicative effects on risk, may account for the genetic susceptibility to prostate cancer. The recessive component would predict the observed higher familial risk for siblings of cases than for fathers, but this could also be due to other factors such as shared lifestyle by siblings, targeted screening effects, and/or non-additive effects of one or more genes.

Identification and Prediction of Drinking Trajectories in Early and Mid-Adolescence

The aim of this study was to identify subgroups of early and mid-adolescents with different drinking trajectories. In addition, we examined whether gender, parental, and peer factors predicted adolescents' membership of these drinking trajectories. We used longitudinal data of 428 families (fathers, mothers, mid-adolescents, and their younger siblings). Latent Class Growth Analyses were performed to identify drinking trajectories. Four drinking trajectories emerged for early adolescents: abstainers, light drinkers, increasers, and heavy drinkers. For mid-adolescents, we identified a fifth group (stable drinkers) in addition to the four trajectories identified for early adolescents. Our results showed that being a boy, having a best friend or father who drinks heavily, and having parents who are permissive toward adolescents' alcohol creates increased risk for both siblings to attend the more heavy drinking trajectories.

Familial risks in nervous-system tumours: a histology-specific analysis from Sweden and Norway

There are limited data available on tumour subtype-specific familial risks for nervous-system tumours. We aimed to provide such data at the population level. We used data from the nationwide Swedish and Norwegian databases on familial cancer to calculate standardised incidence ratios (SIRs) for the familial risk of developing a nervous-system tumour in offspring born after 1931 (Sweden) or 1900 (Norway) whose parents or siblings were probands. 54 195 patients had nervous-system tumours, 22 331 of whom belonged to the offspring generation aged 0-72 years in Sweden and 0-51 years in Norway. Of 709 familial patients in the offspring generation, 438 (61.8%) had a parent affected by a nervous-system tumour (SIR 1.66; 95% CI 1.51-1.82), 236 (33.3%) had a sibling affected by a nervous-system tumour (SIR 2.01; 95% CI 1.76-2.28), and 35 (4.9%) belonged to families with a parent and at least two siblings affected by a nervous-system tumour (multiplex families; SIR 13.40; 95% CI 9.33-18.66). The SIR for glioma was 1.8 (1.5-2.0) when a parent was a proband, but increased to 11.2 (5.7-19.5) in multiplex families. Early-onset neurinoma and haemangioma showed high familial risks; with an SIR for neurinoma of 1.7 (1.4-2.2) for offspring of affected parents, 2.7 (2.0-3.5) for siblings, and 27.2 (13.5-48.8) for multiplex families, and an SIR for haemangioma of 2.4 (1.4-3.8) for offspring of affected parents. Histology-specific population-based familial risks were shown for meningioma (1.6 for offspring of affected parents; 95% CI 1.3-2.0), ependymoma (2.7 for young offspring <20 years; 1.1-5.5), medulloblastoma (4.1 for siblings; 1.7-8.1), and neuroblastoma (3.2 for siblings; 1.1-6.9). Our results suggest a complex genetic background for nervous-system tumours, which differs depending on the age of onset and histological subtype of the tumour. High sibling risks might suggest recessive inheritance. As the high-penetrant multiplex families only accounted for about 5% of familial nervous-system tumours, most familial cases are probably caused by low-penetrance genes. The Nordic Cancer Union, Deutsche Krebshilfe, the Swedish Cancer Society, and the Swedish Council for Working Life and Social Research.

Genome-wide association studies reach hepatology

Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH. Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem of unknown etiology that varies in prevalence among ancestry groups. To identify genetic variants contributing to differences in hepatic fat content, we carried out a genome-wide association scan of nonsynonymous sequence variations ( n =9229) in a population comprising Hispanic, African American and European American individuals. An allele in PNPLA3 (rs738409[G], encoding I148M) was strongly associated with increased hepatic fat levels ( P =5.9×10(−10)) and with hepatic inflammation ( P =3.7×10(−4)). The allele was most common in Hispanics, the group most susceptible to NAFLD; hepatic fat content was more than twofold higher in PNPLA3 rs738409[G] homozygotes than in noncarriers. Resequencing revealed another allele of PNPLA3 (rs6006460[T], encoding S453I) that was associated with lower hepatic fat content in African Americans, the group at lowest risk of NAFLD. Thus, variation in PNPLA3 contributes to ancestry-related and inter-individual differences in hepatic fat content and susceptibility to NAFLD. [Abstract reproduced by permission of Nat Genet 2008;40:1461-1465].

Results of the MHC Fine Mapping Workshop

Type 1 diabetes (T1D) is strongly clustered in families, with an overall sibling risk ratio (λS) of approximately 15. One region (comprised of multiple loci) that contributes greatly to the familial clustering of T1D is the Major His tocompatibility Complex (MHC) on chromosome 6p21. The locus-specific sibling risk ratio (λS) of the MHC region is approximately 3, thereby contributing as much as 40% to the observed familial clustering. Genetic, functional, structural and model studies all suggest that the human leucocyte antigen (HLA) class II genes (HLA-DRB1 and HLA-DQB1) are the major determinants of T1D risk in the MHC region. Despite the recognized effect of HLA class II genes on risk, it is not clear what contributions other genes in this region may make. The Type 1 Diabetes Genetics Consortium (T1DGC) launched an initiative to more comprehensively examine the genetic basis of T1D in the extended MHC region encompassing 4 Mb (between 29 and 34 Mb). Characterization of genes in this region used classical HLA genotyping and a framework map of 66 microsatellite markers and over 3000 single nucleotide polymorphisms (SNPs) in 2321 affected sib-pair families. The reports in this Supplement, sponsored by the T1DGC, reflect multiple analytic approaches applied to a common set of data. Analyses of individual SNPs as well as haplotypes in the region have been performed and have incorporated the effect of the classical HLA class II gene contributions.