Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24.

Prostate cancer is the most prevalent noncutaneous cancer in males in developed regions, with African American men having among the highest worldwide incidence and mortality rates. Here we report a second genetic variant in the 8q24 region that, in conjunction with another variant we recently discovered, accounts for about 11%-13% of prostate cancer cases in individuals of European descent and 31% of cases in African Americans. We made the current discovery through a genome-wide association scan of 1,453 affected Icelandic individuals and 3,064 controls using the Illumina HumanHap300 BeadChip followed by four replication studies. A key step in the discovery was the construction of a 14-SNP haplotype that efficiently tags a relatively uncommon (2%-4%) susceptibility variant in individuals of European descent that happens to be very common (approximately 42%) in African Americans. The newly identified variant shows a stronger association with affected individuals who have an earlier age at diagnosis.

Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes.

We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1beta), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes.

Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer.

Familial clustering studies indicate that breast cancer risk has a substantial genetic component. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then tested selected SNPs in five replication sample sets. Overall, we studied 4,554 affected individuals and 17,577 controls. Two SNPs consistently associated with breast cancer: approximately 25% of individuals of European descent are homozygous for allele A of rs13387042 on chromosome 2q35 and have an estimated 1.44-fold greater risk than noncarriers, and for allele T of rs3803662 on 16q12, about 7% are homozygous and have a 1.64-fold greater risk. Risk from both alleles was confined to estrogen receptor-positive tumors. At present, no genes have been identified in the linkage disequilibrium block containing rs13387042. rs3803662 is near the 5' end of TNRC9 , a high mobility group chromatin-associated protein whose expression is implicated in breast cancer metastasis to bone.

A common variant associated with prostate cancer in European and African populations.

With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.

Genetics of gene expression and its effect on disease.

Common human diseases result from the interplay of many genes and environmental factors. Therefore, a more integrative biology approach is needed to unravel the complexity and causes of such diseases. To elucidate the complexity of common human diseases such as obesity, we have analysed the expression of 23,720 transcripts in large population-based blood and adipose tissue cohorts comprehensively assessed for various phenotypes, including traits related to clinical obesity. In contrast to the blood expression profiles, we observed a marked correlation between gene expression in adipose tissue and obesity-related traits. Genome-wide linkage and association mapping revealed a highly significant genetic component to gene expression traits, including a strong genetic effect of proximal (cis) signals, with 50% of the cis signals overlapping between the two tissues profiled. Here we demonstrate an extensive transcriptional network constructed from the human adipose data that exhibits significant overlap with similar network modules constructed from mouse adipose data. A core network module in humans and mice was identified that is enriched for genes involved in the inflammatory and immune response and has been found to be causally associated to obesity-related traits.

A variant associated with nicotine dependence, lung cancer and peripheral arterial disease.

Smoking is a leading cause of preventable death, causing about 5 million premature deaths worldwide each year. Evidence for genetic influence on smoking behaviour and nicotine dependence (ND) has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important to public health. Smoking is the major risk factor for lung cancer (LC) and is one of the main risk factors for peripheral arterial disease (PAD). Here we identify a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in our sample of smokers. The same variant was associated with ND in a previous genome-wide association study that used low-quantity smokers as controls, and with a similar approach we observe a highly significant association with ND. A comparison of cases of LC and PAD with population controls each showed that the variant confers risk of LC and PAD. The findings provide a case study of a gene-environment interaction, highlighting the role of nicotine addiction in the pathology of other serious diseases.

Psychometric properties of the Icelandic NEO-FFI in a general population sample compared to a sample recruited for a study on the genetics of addiction.

Personality traits are major determinants of social behavior influencing various diseases including addiction. Twin and family studies suggest personality and addiction to be under genetic influence. Identification of DNA susceptibility variants relies on valid and reliable phenotyping approaches. We present results of psychometric testing of the Icelandic NEO-FFI in a population sample (N=657) and a sample recruited for a study on addiction genetics (N=3,804). The Icelandic NEO-FFI demonstrated internal consistency and temporal stability. Factor analyses supported the five-factor structure. Icelandic norms were compared to American norms and language translations selected for geographical and cultural proximity to Iceland. Multiple discriminant function analysis using NEO-FFI trait scores and gender as independent variables predicted membership in recruitment groups for 47.3% of addiction study cases (N=3,804), with accurate predictions made for 69.5% of individuals with treated addiction and 43.3% of their first-degree relatives. Correlations between NEO-FFI scores and the discriminant function suggested a combination of high neuroticism, low conscientiousness and low agreeableness predicted membership in the Treated group.

A common inversion under selection in Europeans.

A refined physical map of chromosome 17q21.31 uncovered a 900-kb inversion polymorphism. Chromosomes with the inverted segment in different orientations represent two distinct lineages, H1 and H2, that have diverged for as much as 3 million years and show no evidence of having recombined. The H2 lineage is rare in Africans, almost absent in East Asians but found at a frequency of 20% in Europeans, in whom the haplotype structure is indicative of a history of positive selection. Here we show that the H2 lineage is undergoing positive selection in the Icelandic population, such that carrier females have more children and have higher recombination rates than noncarriers.

Variants conferring risk of atrial fibrillation on chromosome 4q25.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left-right asymmetry of the heart.

Association of variants at UMOD with chronic kidney disease and kidney stones-role of age and comorbid diseases.

Chronic kidney disease (CKD) is a worldwide public health problem that is associated with substantial morbidity and mortality. To search for sequence variants that associate with CKD, we conducted a genome-wide association study (GWAS) that included a total of 3,203 Icelandic cases and 38,782 controls. We observed an association between CKD and a variant with 80% population frequency, rs4293393-T, positioned next to the UMOD gene (GeneID: 7369) on chromosome 16p12 (OR = 1.25, P = 4.1x10(-10)). This gene encodes uromodulin (Tamm-Horsfall protein), the most abundant protein in mammalian urine. The variant also associates significantly with serum creatinine concentration (SCr) in Icelandic subjects (N = 24,635, P = 1.3 x 10(-23)) but not in a smaller set of healthy Dutch controls (N = 1,819, P = 0.39). Our findings validate the association between the UMOD variant and both CKD and SCr recently discovered in a large GWAS. In the Icelandic dataset, we demonstrate that the effect on SCr increases substantially with both age (P = 3.0 x 10(-17)) and number of comorbid diseases (P = 0.008). The association with CKD is also stronger in the older age groups. These results suggest that the UMOD variant may influence the adaptation of the kidney to age-related risk factors of kidney disease such as hypertension and diabetes. The variant also associates with serum urea (P = 1.0 x 10(-6)), uric acid (P = 0.0064), and suggestively with gout. In contrast to CKD, the UMOD variant confers protection against kidney stones when studied in 3,617 Icelandic and Dutch kidney stone cases and 43,201 controls (OR = 0.88, P = 5.7 x 10(-5)).

Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.

We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor alpha (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case:control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2 x 10(-3)), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9 x 10(-4)) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9 x 10(-7)), was without significant heterogeneity between ancestries (P(het) = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.

Toward higher-performance bionic limbs for wider clinical use.

Most prosthetic limbs can autonomously move with dexterity, yet they are not perceived by the user as belonging to their own body. Robotic limbs can convey information about the environment with higher precision than biological limbs, but their actual performance is substantially limited by current technologies for the interfacing of the robotic devices with the body and for transferring motor and sensory information bidirectionally between the prosthesis and the user. In this Perspective, we argue that direct skeletal attachment of bionic devices via osseointegration, the amplification of neural signals by targeted muscle innervation, improved prosthesis control via implanted muscle sensors and advanced algorithms, and the provision of sensory feedback by means of electrodes implanted in peripheral nerves, should all be leveraged towards the creation of a new generation of high-performance bionic limbs. These technologies have been clinically tested in humans, and alongside mechanical redesigns and adequate rehabilitation training should facilitate the wider clinical use of bionic limbs.

An impairment-specific hip exoskeleton assistance for gait training in subjects with acquired brain injury: a feasibility study.

This study was designed to investigate the feasibility and the potential effects on walking performance of a short gait training with a novel impairment-specific hip assistance (iHA) through a bilateral active pelvis orthosis (APO) in patients with acquired brain injury (ABI). Fourteen subjects capable of independent gait and exhibiting mild-to-moderate gait deficits, due to an ABI, were enrolled. Subjects presenting deficit in hip flexion and/or extension were included and divided into two groups based on the presence (group A, n = 6) or absence (group B, n = 8) of knee hyperextension during stance phase of walking. Two iHA-based profiles were developed for the groups. The protocol included two overground gait training sessions using APO, and two evaluation sessions, pre and post training. Primary outcomes were pre vs. post-training walking distance and steady-state speed in the 6-min walking test. Secondary outcomes were self-selected speed, joint kinematics and kinetics, gait symmetry and forward propulsion, assessed through 3D gait analysis. Following the training, study participants significantly increased the walked distance and average steady-state speed in the 6-min walking tests, both when walking with and without the APO. The increased walked distance surpassed the minimal clinically important difference for groups A and B, (respectively, 42 and 57 m > 34 m). In group A, five out of six subjects had decreased knee hyperextension at the post-training session (on average the peak of the knee extension angle was reduced by 36%). Knee flexion during swing phase increased, by 16% and 31%, for A and B groups respectively. Two-day gait training with APO providing iHA was effective and safe in improving walking performance and knee kinematics in ABI survivors. These preliminary findings suggest that this strategy may be viable for subject-specific post-ABI gait rehabilitation.

Lessons from the past: familial aggregation analysis of fatal pandemic influenza (Spanish flu) in Iceland in 1918.

The pandemic influenza of 1918 (Spanish flu) killed 21-50 million people globally, including in Iceland, where the characteristics and spread of the epidemic were well documented. It has been postulated that genetic host factors may have contributed to this high mortality. We identified 455 individuals who died of the Spanish flu in Iceland during a 6-week period during the winter of 1918, representing >92% of all fatal domestic cases mentioned by historical accounts. The highest case fatality proportion was 2.8%, and peak excess mortality was 162/100,000/week. Fatality proportions were highest among infants, young adults, and the elderly. A genealogical database was used to study relatedness and relative risk (RR) of the fatal influenza victims and relatives of their unaffected mates. The significance of these RR computations was assessed by drawing samples randomly from the genealogical database matched for age, sex, and geographical distribution. Familial aggregation of fatalities was seen, with RRs for death ranging from 3.75 for first-degree relatives (P < 0.0001) to 1.82 (P = 0.005), 1.12 (P = 0.252), and 1.47 (P = 0.0001) for second- to fourth-degree relatives of fatal influenza victims, respectively. The RRs within the families of unaffected mates of fatal influenza victims were 2.95 (P < 0.0001), 1.27 (P = 0.267), 1.35 (P = 0.04), and 1.42 (P = 0.001), for first- to fourth-degree relatives, respectively. In conclusion, the risk of death from the Spanish flu was similar within families of patients who succumbed to the illness and within families of their mates who survived. Our data do not provide conclusive evidence for the role of genetic factors in susceptibility to the Spanish flu.

A genetic risk factor for periodic limb movements in sleep.

BACKGROUND: The restless legs syndrome (RLS) is a common neurologic disorder characterized by an irresistible urge to move the legs. It is a major cause of sleep disruption. Periodic limb movements in sleep are detectable in most patients with RLS and represent an objective physiological metric. METHODS: To search for sequence variants contributing to RLS, we performed a genomewide association study and two replication studies. To minimize phenotypic heterogeneity, we focused on patients with RLS who had objectively documented periodic limb movements in sleep. We measured serum ferritin levels, since iron depletion has been associated with the pathogenesis of RLS. RESULTS: In an Icelandic discovery sample of patients with RLS and periodic limb movements in sleep, we observed a genomewide significant association with a common variant in an intron of BTBD9 on chromosome 6p21.2 (odds ratio, 1.8; P=2x10(-9)). This association was replicated in a second Icelandic sample (odds ratio, 1.8; P=4x10(-4)) and a U.S. sample (odds ratio, 1.5; P=4x10(-3)). With this variant, the population attributable risk of RLS with periodic limb movements was approximately 50%. An association between the variant and periodic limb movements in sleep without RLS (and the absence of such an association for RLS without periodic limb movements) suggests that we have identified a genetic determinant of periodic limb movements in sleep (odds ratio, 1.9; P=1x10(-17)). Serum ferritin levels were decreased by 13% per allele of the at-risk variant (95% confidence interval, 5 to 20; P=0.002). CONCLUSIONS: We have discovered a variant associated with susceptibility to periodic limb movements in sleep. The inverse correlation of the variant with iron stores is consistent with the suspected involvement of iron depletion in the pathogenesis of the disease.

A strong familiality of ankylosing spondylitis through several generations.

OBJECTIVE: To elucidate the familiality of ankylosing spondylitis (AS) in Iceland. METHODS: The Icelandic genealogy database and population-wide data on all living Icelanders diagnosed as having AS (n=280), who previously had taken part in an epidemiological study on the prevalence of AS in Iceland, were included in the study. Identification of all interpatient relationships in the genealogy database allowed calculation of estimates of the RR for AS in the first-degree relatives (FDRs) to fourth-degree relatives of patients. For each AS proband, 1000 sets of matched Icelandic subjects in the genealogy database were used as controls. RESULTS: FDRs, second-degree and third-degree relatives had RRs of 75.5, 20.2 and 3.5, respectively (all p values <0.0001), indicating a significantly increased risk for relatives of the patients with AS to develop AS, suggesting a strong heritable factor, while the fourth-degree relatives had a RR of 1.04 (p=0.476) for having AS. CONCLUSIONS: Patients with AS in Iceland are significantly more related to each other than to randomly sampled control subjects. This is in agreement with previous reports on the familiality of AS, but the present study has more power and extends over larger familiar cohorts than previously reported.

Prevalence and clinical characteristics of ankylosing spondylitis in Iceland - a nationwide study.

OBJECTIVES: To determine the prevalence and clinical characteristics of ankylosing spondylitis (AS) in the Icelandic population, which carries a high prevalence of HLA-B27. METHODS: A nationwide search was performed by screening hospital records and private rheumatology services for cases of AS in association with an on-going genetic study. Individuals diagnosed with AS according to the modified New York criteria were asked to participate in the study by answering a standardised questionnaire and to undergo an interview and clinical evaluation. RESULTS: A total of 256 individuals fulfilled the modified New York classification criteria for AS (169 male, 87 female); 84% of these individuals were HLA-B27 positive vs. 15% in the population (p<10-16). Of those contacted 223 patients (87.1%) answered the standardised questionnaire and were included in the study. The prevalence of AS in Iceland was 0.13% (CI 0.11-0.14%). A highly conservative prevalence number, based only on clinically evaluated patients, gave prevalence of 0.10% (CI 0.09-0.11%). Mean age at onset of symptoms was 24+/-8 years and at diagnosis 32.1+/-10.2 for male and 34.2+/-10.1 for female patients (not significant). Female patients more often had arthritis in peripheral joints and male patients were more often diagnosed with iritis. Prostatitis was experienced by 27% of male patients. CONCLUSIONS: AS is less common in the Icelandic population than reported in various Caucasian populations with a similar prevalence of HLA-B27.

Motorized Biomechatronic Upper and Lower Limb Prostheses-Clinically Relevant Outcomes.

People with major limb amputations are severely impaired when it comes to activity, body structure and function, as well as participation. Demographic statistics predict a dramatic increase of this population and additional challenges with their increasing age and higher levels of amputation. Prosthetic use has been shown to have a positive impact on mobility and depression, thereby affecting the quality of life. Biomechatronic prostheses are at the forefront of prosthetic development. Actively powered designs are now regularly used for upper limb prosthetic fittings, whereas for lower limbs the clinical use of actively powered prostheses has been limited to a very low number of applications. Actively powered prostheses enhance restoration of the lost physical functions of an amputee but are yet to allow intuitive user control. This paper provides a review of the status of biomechatronic developments in upper and lower limb prostheses in the context of the various challenges of amputation and the clinically relevant outcomes. Whereas most of the evidence regarding lower limb prostheses addresses biomechanical issues, the evidence for upper limb prostheses relates to activities of daily living (ADL) and instrumental ADL through diverse outcome measures and tools.

The BARD1 Cys557Ser variant and breast cancer risk in Iceland.

BACKGROUND: Most, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer. METHODS AND FINDINGS: The Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.11-3.01, p = 0.014). The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22-4.75, p = 0.015). Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16-8.40, p = 0.046) in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors of contemporary carriers lived in a single county in the southeast of Iceland and that all carriers shared a SNP haplotype, which is suggestive of a founder event. Cys557Ser was found on the same SNP haplotype background in the HapMap Project CEPH sample of Utah residents. CONCLUSIONS: Our findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation.

Validity of self-report and informant rating scales of adult ADHD symptoms in comparison with a semistructured diagnostic interview.

In a study of ADHD symptoms in the relatives of probands diagnosed with ADHD, the validity of self-reported and informant-reported symptoms in childhood and adulthood was investigated with a semistructured diagnostic interview, the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) adapted for adults, as a criterion. The participating relatives were 80 women and 46 men aged 17 to 77. Rating scales based on the Diagnostic and Statistical Manual of Mental Disorders (4th ed.) were completed by participants and informants. Internal consistency of the scales and interrater reliabilities of the diagnostic interview were satisfactory. Correlations between ratings across sources of information supported convergent and divergent validity. Self-report scales and informant scales predicted interview-based diagnoses in childhood and adulthood with adequate sensitivities and specificities. It was concluded that the rating scales have good psychometric properties, at least in at-risk populations.