Time trends and geographical patterns in suicide among Greenland Inuit.

BACKGROUND: Between 1980 and 2018 Greenland has had one of the highest suicide rates in the world with an average rate of 96 suicides per 100,000 people annually. The aim of this study is to investigate suicide rates in Greenland according to age, birth cohort, period, sex, place of residence and suicide method from 1970 until 2018. METHODS: Suicide rates were examined using register and census data from 1970-2018 among Greenland Inuit. Rates were calculated by Poisson regression in Stata and by use of Excel. In analyses of the period trends, rates were standardized according to the World Standard Population 2000-2025. RESULTS: The suicide rate has been declining since a peak at 120 suicides per 100,000 people annually in the 1980s but remained high at a rate of 81.3 suicides per 100,000 people annually from 2015-2018. Descriptive analyses point to the decrease in male suicides as the primary factor for the overall decreasing rates while the rate among women has been increasing. Simultaneously, the proportion of women who used a violent suicide method increased from 60% in 1970-1979 to 90% in 2010-2018. The highest rates are seen among young people, especially young men aged 20-24 years and youth suicide rates increased with later birth cohorts. When the rates started to increase in the 1980s both the capital Nuuk and East Greenland had the highest rates. Since then, the rate in Nuuk has declined while the rate in East Greenland was three times the national rate from 2015-2018. CONCLUSIONS: From 1970 to 1989 the suicide rate increased from 28.7 to 120.5 per 100,000 people mirroring a rapid societal transition in the post-colonial period. The rate has slowly declined from the peak in the 1980s but remains at a very high level. Young people in general are at risk, but the steady increase in the rate among women is worrying and there is a need to investigate underlying causes for this development.

Parents' perspectives on preparing for parenthood: a qualitative study on Greenland's universal parenting programme MANU 0-1 year.

BACKGROUND: The transition to parenthood has received increasing attention in research, partly due to evidence pointing out the crucial developmental period of a child's first thousand days. Parenting programmes aim to prepare and support families in their transition and distress. For a programme to be implemented successfully it is important to consider parents' needs and resources. Bringing parents' perspectives and experiences to the forefront of the implementation of the Greenlandic parenting programme MANU 0-1 Year (MANU) is important for determining if the programme can meet its aim of contributing to thriving families. This study aims to investigate how parents' notions and experiences of parenthood are reflected and challenged in MANU. METHOD: Data were collected in three of Greenland's five municipalities. Qualitative interviews were held with 38 mothers and 12 fathers either individually or as couples: a total of 40 interviews. Additionally, a Sharing Circle with three fathers was held. Interviews were in Greenlandic or Danish. A thematic, inductive analysis was applied. RESULTS: In their transition to parenthood, participants experienced a reprioritisation of their life and changes in their network. It is important to parents that their child experiences security and care, and participants describe this in contrast to their own childhood. Community is the most important value in child-rearing. Conversations and advice from family members and friends are mentioned as a means to prepare for birth and parenthood. Additionally, conversations with midwives and MANU sessions were also used for preparation. Parents appreciated learning from and listening to other parents in MANU sessions. However, accessing MANU depends on the individual parent's interest and ability to attend sessions. CONCLUSIONS: Parents' notions and experiences of parenthood are addressed in the programme, but the use of MANU depends on the parents' attendance and how it is organised and locally offered. The study suggests that MANU has the possibility to create a space for parents to reflect and prepare. However, for MANU to be universal as intended and to reach both mother and father the facilitation of sessions could be revisited.

Social determinants of dietary patterns, food basket costs and expenditure on alcohol and tobacco amongst Greenland Inuit.

OBJECTIVE: Dietary transition, obesity and risky use of alcohol and tobacco are challenges to public health among indigenous peoples. The aim of the article was to explore the role of social position in dietary patterns and expenditures on food and other commodities. DESIGN: Countrywide population health survey. SETTING: Greenland. PARTICIPANTS: 2436 Inuit aged 15+ years. RESULTS: Less than half of the expenditures on commodities (43 %) were used to buy nutritious food, and the remaining to buy non-nutritious food (21 %), alcoholic beverages (18 %) and tobacco (18 %). Participants were classified according to five dietary patterns. The cost of a balanced diet and an unhealthy diet was similar, but the cost per 1000 kJ was higher and the energy consumption was lower for the balanced diet. Participants with low social position chose the unhealthy pattern more often than those with high social position (40 % v. 24 %; P < 0·0001), whereas those with high social position more often chose the balanced alternative. Participants with low social position spent less money on the total food basket than those with high social position but more on non-nutritious food, alcohol and tobacco. CONCLUSIONS: Cost seems to be less important than other mechanisms in the shaping of social dietary patterns and the use of alcohol and tobacco among the Inuit in Greenland. Rather than increasing the price of non-nutritious food or subsidising nutritious food, socially targeted interventions and public health promotion regarding food choice and prevention of excessive alcohol use and smoking are needed to change the purchase patterns.

Association of food insecurity with dietary patterns and expenditure on food, alcohol and tobacco amongst indigenous Inuit in Greenland: results from a population health survey.

BACKGROUND: Amongst the indigenous Greenlandic Inuit, the experience of food insecurity has been attributed to a lack of money to buy enough food of sufficient quality to sustain a family, although a preference for alcohol and tobacco over food has also been cited. The purpose of the article was to compare dietary patterns and expenditure on food, alcoholic beverages and tobacco between survey participants who reported food insecurity and those who did not. METHODS: A countrywide cross-sectional health survey was carried out among 1886 adult Greenlandic Inuit in 2018. Diet was estimated by a food frequency questionnaire. Food insecurity status was based on the household hunger scale. Analyses were carried out by univariate general linear models adjusted for age, sex and social position. RESULTS: Nine percent of the participants reported food insecurity. Food insecurity was higher among younger participants, men and participants with low social position. Food insecure participants more often chose an unhealthy dietary pattern (43% vs. 32%) and they reported a higher energy intake. The food insecure spent the same amount of money on food as other participants but less on nutritious food and more on non-nutritious food. The cost per kilojoule (kJ) of the food of the food insecure was lower than that of the food secure (DKK 8.0 and 9.0 per 1000 kJ, respectively). The food insecure participants also spent considerably more on alcohol and tobacco. CONCLUSIONS: The results suggest that it is not only unemployment and lack of money that creates food insecurity and unhealthy dietary patterns in Greenland. Food insecure participants gave higher priority to buying non-nutritious food, alcohol and tobacco than did food secure participants. There seems to be at least two population subgroups in Greenland with poverty and substance use, respectively, as the immediate determinants for food insecurity. The results are important for the design of interventions against food insecurity and unhealthy dietary patterns.

Estimating narrow-sense heritability using family data from admixed populations.

Estimating total narrow-sense heritability in admixed populations remains an open question. In this work, we used extensive simulations to evaluate existing linear mixed-model frameworks for estimating total narrow-sense heritability in two population-based cohorts from Greenland, and compared the results with data from unadmixed individuals from Denmark. When our analysis focused on Greenlandic sib pairs, and under the assumption that shared environment among siblings has a negligible effect, the model with two relationship matrices, one capturing identity by descent and one capturing identity by state, returned heritability estimates close to the true simulated value, while using each of the two matrices alone led to downward biases. When phenotypes correlated with ancestry, heritability estimates were inflated. Based on these observations, we propose a PCA-based adjustment that recovers the true simulated heritability. We use this knowledge to estimate the heritability of ten quantitative traits from the two Greenlandic cohorts, and report differences such as lower heritability for height in Greenlanders compared with Europeans. In conclusion, narrow-sense heritability in admixed populations is best estimated when using a mixture of genetic relationship matrices on individuals with at least one first-degree relative included in the sample.

Whole blood mercury and the risk of cardiovascular disease among the Greenlandic population.

BACKGROUND: Studies have found mercury to be associated with cardiovascular disease (CVD), however, primarily in populations with low exposure. The highest levels, and variations in the levels, of whole blood mercury (WBM) worldwide have been found in Greenland. We prospectively assessed the association between WBM and the risk of developing CVD in the Greenlandic population. METHODS: We assessed the effects of WBM levels on incident CVD among 3083 Greenlandic Inuit, participating in a population-based cohort study conducted from 2005 to 2010. WBM was measured at baseline. Participants were followed in the National Patient Registries for Denmark and Greenland and in the causes of death register for CVD events from inclusion in the study until CVD event, emigration, death or end of follow-up (30/9-2013). Using Cox regression analyses, we calculated the incidence rates and the hazard ratio of CVD events according to WBM levels. Potential interactions with sex were also investigated. RESULTS: The highest levels of WBM were found in men, who had a significantly higher median level (19 µg/L (IQR:1-44)), compared with women (15 µg/L (IQR: 1-32), (p < 0.001)). The crude hazard ratio (HR) for incident CVD was 1.00 (95% CI 1.00-1.00) for 5 µg/l increase in WBM. After adjusting for several potential confounders, there was still no association between WBM and incident CVD (HR 0.99; 95%CI:0.99-1.00). We found no interactions with sex. CONCLUSIONS: In a population with high levels of WBM, we found no association between WBM and the risk of developing CVD in Greenland.

A nationwide study of health-related quality of life, stress, pain or discomfort and the use of medicine among problem gamblers.

AIM: The aim of this study was to investigate the associations between problem gambling and health-related quality of life, stress, pain or discomfort and the use of analgesics and sleeping pills. METHODS: Data derives from the Danish Health and Morbidity Survey 2010. The survey was based on a random sample of 25,000 adult Danes (response rate: 61%), and data were collected via a self-administered questionnaire. The Lie/Bet Questionnaire was used as the screening instrument for problem gambling. Respondents were categorised as current, previous or non-problem gamblers. The questionnaire also included topics such as health-related quality of life (Short Form-12), perceived stress, pain and discomforts within the past two weeks, as well as the use of medication within the past two weeks. RESULTS: Current problem gambling was strongly associated with negative outcomes such as poor mental health, high perception of stress, headache, fatigue and sleeping problems. Furthermore, previous problem gambling was generally associated with poorer health outcomes. Thus, current and previous problem gamblers had 2.36 times (95% confidence interval [CI] 1.44-3.87) and 1.66 times (95% CI 1.07-2.55) higher odds than non-problem gamblers of reporting fair or poor health, respectively. The data revealed no clear association between problem gambling and the use of analgesics. CONCLUSIONS: Both current and previous problem gambling were negatively associated with physical and mental-health problems. Health professionals should be alert to any signs of these complicating factors when planning the treatment of problem gamblers.

Problem Gambling Associated with Violent and Criminal Behaviour: A Danish Population-Based Survey and Register Study.

This study compares the number of criminal charges among problem gamblers (N = 384) and non-problem gamblers including non-gamblers (N = 18,241) and examines whether problem gambling is more strongly associated with income-generating crimes like theft, fraud and forgery than other types of crimes such as violent crimes. A cohort study was carried out, based on data from the Danish Health and Morbidity Surveys in 2005 and 2010, which were linked at the individual level with data from The Danish National Criminal Register. Multiple logistic regression analyses were used to determine the association between problem gambling and charges for different categories of crime. We found that problem gamblers had significantly higher odds of being charged than non-problem gamblers (adjusted odds ratio 1.5; 95 % confidence interval 1.1-1.9). The odds ratio for economic crime charges was 2.6 (1.5-4.5), for violence charges 2.2 (1.1-4.5), and for drug charges 3.7 (1.7-8.0). For road traffic charges the odds ratio was 1.3 (1.0-1.8). Hence, there was a strong association between problem gambling and being charged except for road traffic charges; however the association was not stronger for economic charges than for violence and drug charges.

Increasing health inequality among Inuit in Greenland from 1993 to 2018: Different patterns for household assets, urbanization and a sociocultural index as indicators of social position.

Income inequality affects population health and wellbeing negatively. In Greenland, health inequality has been shown to exist among social groups, regionally and according to urbanization, and between Inuit and migrants from Denmark. The purpose of the study was to compare the changes in health inequality from 1993 to 2018 according to three measures of social position, i.e. a socioeconomic measure (household assets), a measure of urbanization and a composite sociocultural index. We hypothesized that social inequality in health increased parallel to the increasing economic inequality in Greenland. The sample was based on four population health surveys conducted among the Inuit in Greenland in 1993, 2005-2010, 2014 and 2018. The total number of interviews was 9024 and the total number of individuals interviewed was 5829, as participants were invited to several surveys as part of a cohort. As statistical measure of social disparity we used the slope index of inequality (SII) adjusted for age and sex. Analyses were performed with daily smoking, suicidal thoughts and obesity as health outcomes. Daily smoking was most prevalent among participants with low social position whereas obesity was most prevalent among participants with high social position. With household assets as indicator of social position, the results showed high and increasing social inequality for both daily smoking and obesity. Social inequality for daily smoking increased over time also for urbanization and the sociocultural index. The hypothesis that social inequality increased over time was thus confirmed for daily smoking and obesity but not for suicidal thoughts. With the results from the present study there is solid evidence to guide prevention and health care towards social equality in health.

Developing the ACEIG-scale: An adverse childhood experience scale for Inuit youth in Greenland.

BACKGROUND: Adverse Childhood Experiences (ACEs) have been identified as a major public health challenge in Greenland. No previous studies have created a multi-item ACE- scale among an Arctic Indigenous population. OBJECTIVE: To develop a multi-item ACE-scale among Inuit youth in Greenland (the ACEIG scale). METHODS: The ACEIG scale was created with data from the 'Wellbeing among Inuit youth in Greenland'-survey. Scale items were based on a recognised ACE-scale and further adapted to the context of Inuit youth in Greenland by adding items relevant for the population. The scale was validated through item response theory (IRT) and reliability was assessed by Cronbach's alpha. RESULTS: Four items relevant for Inuit youth in Greenland were added to the recognised ACE scale (bullying, death of parent, gambling problems in close family, and suicide in close relations). The scale was reduced by IRT, as three items (bullying, divorce of parents and parents passing away) exceeded the difficulty index threshold. The ACEIG scale therefore consists of 10 items: alcohol problems in close family, marijuana use in close family, domestic violence, being victim of physical violence, being victim of psychological violence, any type of sexual abuse, sexual abuse (intercourse), sexual abuse (more than once), suicide in close relations, and gambling problems in close family. Cronbach's alpha was 0.7. CONCLUSION: The ACEIG scale includes 10 items with acceptable reliability. The scale can inform future screening tools to identify vulnerable youth and target interventions. Future studies should investigate the association between the ACEIG scale and health outcomes.

A qualitative study of the implementation and organization of the national Greenlandic addiction treatment service.

Background: Alcohol and cannabis use constitutes the major public health problems in Greenland. Thus, it is important to assess if Allorfik, a new national outpatient addiction treatment service introduced in 2016, was implemented successfully and how it is perceived. Allorfik introduced local treatment centers offering a treatment methodology (motivational interviewing and cognitive therapy) new to addiction treatment in Greenland with limited evidence from Indigenous populations such as the Greenlandic. The present study investigates the implementation of Allorfik from the perspective of those engaged in the process and the field. Methods: Data consisted of transcribed interviews with 23 individuals from both Allorfik and organizations collaborating with or supposed to collaborate with Allorfik. The theme of the interviews was their perspectives on the implementation process, enablers, and obstacles in the process and how Allorfik was performing at the time of the interview. The interview guide was informed by implementation theory. The transcribed material was analyzed using a general inductive approach. Results: The analysis resulted in three overall and interconnected themes, namely, implementation, collaborations, and challenges. The implementation was overall considered a success by the interviewees as all components were implemented as planned with a few adaptions, e.g., a treatment guideline update. The collaborations are considered challenging but important to all interviewees. Collaborations seem to rely on personal commitment as opposed to well-defined structures, making it unstable and vulnerable to changes in staff. One of the main challenges highlighted by the interviewees is the number of problems other than addiction among people in treatment, which makes addiction treatment and recovery difficult to achieve. Nevertheless, the high levels of other problems being treated in Allorfik highlights the need for easily accessible therapy as many find that Allorfik is the only place to turn to in times of crisis. Conclusion: Allorfik seems to have been implemented in accordance with original intentions and plans for addiction treatment service but has also become more than just a service for addiction treatment with easy access in a country with vast distances and limited resources.

GWAS of lipids in Greenlanders finds association signals shared with Europeans and reveals an independent PCSK9 association signal.

Perturbation of lipid homoeostasis is a major risk factor for cardiovascular disease (CVD), the leading cause of death worldwide. We aimed to identify genetic variants affecting lipid levels, and thereby risk of CVD, in Greenlanders. Genome-wide association studies (GWAS) of six blood lipids, triglycerides, LDL-cholesterol, HDL-cholesterol, total cholesterol, as well as apolipoproteins A1 and B, were performed in up to 4473 Greenlanders. For genome-wide significant variants, we also tested for associations with additional traits, including CVD events. We identified 11 genome-wide significant loci associated with lipid traits. Most of these loci were already known in Europeans, however, we found a potential causal variant near PCSK9 (rs12117661), which was independent of the known PCSK9 loss-of-function variant (rs11491147). rs12117661 was associated with lower LDL-cholesterol (ßSD(SE) = -0.22 (0.03), p = 6.5 × 10-12) and total cholesterol (-0.17 (0.03), p = 1.1 × 10-8) in the Greenlandic study population. Similar associations were observed in Europeans from the UK Biobank, where the variant was also associated with a lower risk of CVD outcomes. Moreover, rs12117661 was a top eQTL for PCSK9 across tissues in European data from the GTEx portal, and was located in a predicted regulatory element, supporting a possible causal impact on PCSK9 expression. Combined, the 11 GWAS signals explained up to 16.3% of the variance of the lipid traits. This suggests that the genetic architecture of lipid levels in Greenlanders is different from Europeans, with fewer variants explaining the variance.

Gambling behavior and problem gambling reflecting social transition and traumatic childhood events among Greenland Inuit: a cross-sectional study in a large indigenous population undergoing rapid change.

An increase in social pathologies is a key feature in indigenous populations undergoing transition. The Greenland Inuit are a large indigenous population constituting a majority in their own country, which makes it possible to investigate differences within the population. This led us to study gambling behavior and problem gambling among Greenland Inuit in relation to the ongoing social transition and traumatic events during childhood. A large representative cross-sectional study was conducted among Greenland Inuit (n = 2,189). Data was collected among adults (18+) in 9 towns and 13 villages in Greenland from 2005 to 2010. Problem gambling, gambling behavior and traumatic childhood events were measured through a self-administered questionnaire. The lie/bet screen was used to identify past year and lifetime problem gambling. Social transition was measured as place of residence and a combination of residence, education and occupation. The lifetime prevalence of problem gambling was 16 % among men and 10 % among women (p < 0.0001); and higher in towns (19 %) compared to the capital of Nuuk (11 %) and in villages (12 %) (men only, p = 0.020). Lifetime problem gambling was associated with social transition (p = 0.023), alcohol problems in childhood home (p = 0.001/p = 0.002) and sexual abuse in childhood (women only, p = 0.030). A comparably high prevalence of lifetime problem gambling among Greenland Inuit adds problem gambling to the list of social pathologies in Greenland. A significant association between lifetime problem gambling, social transition and traumatic childhood events suggests people caught between tradition and modern ways of life are more vulnerable to gambling problems.

Muscular strength, mobility in daily life and mental wellbeing among older adult Inuit in Greenland. The Greenland population health survey 2018.

The purpose was to analyse the association of muscular strength, muscle pain and reduced mobility in daily life with mental wellbeing among older Inuit men and women in Greenland. Data (N = 846) was collected as part of a countrywide cross-sectional health survey in 2018. Hand grip strength and 30-seconds chair stand test were measured according to established protocols. Mobility in daily life was assessed by five questions about the ability to perform specific activities of daily living. Mental wellbeing was assessed by questions about self-rated health, life satisfaction and Goldberg's General Health Questionnaire. In binary multivariate logistic regression models adjusted for age and social position, muscular strength (OR 0.87-0.94) and muscle pain (OR 1.53-1.79) were associated with reduced mobility. In fully adjusted models, muscle pain (OR 0.68-0.83) and reduced mobility (OR 0.51-0.55) but were associated with mental wellbeing. Chair stand score was associated with life satisfaction (OR 1.05). With an increasingly sedentary lifestyle, increasing prevalence of obesity and increasing life expectancy the health consequences of musculoskeletal dysfunction are expected to grow. Prevention and clinical handling of poor mental health among older adults need to consider reduced muscle strength, muscle pain and reduced mobility as important determinants.

Parents' perspectives on the role of kin in child-rearing: a qualitative study on Greenland's universal parenting programme MANU.

Nurturing care and protection from parents and community in the early years of life are fundamental for a child's development. The article aims to explore what relations parents see as meaningful in their child's upbringing and how these are shaped, and how these perspectives are reflected in MANU. MANU is a universal parenting programme in Greenland. Ten of 40 interviews with parents were selected for the analysis of this article's objective. Five grandparents were interviewed. Grandparents are the child's closest extended family members and provide support to parents. Parents placed between one to 19 extended family members in their child's network. Eating and being in nature together, along with familial and intergenerational connectedness, were deemed valuable and important aspects in child-rearing. Parents' own experiences in childhood can influence and complicate how parents place their new family within the extended family. The MANU materials address aspects in the role of kin that parents and grandparents described in interviews. The format and delivery of MANU aims to be universal and mostly addresses Western epistemologies, but both Western and Inuit epistemologies coexists in Greenland. This article creates a window into the existing context parents navigate in. It is important that initiatives are built within this context to ensure they are relevant to families.

A systematic review on risk and protective factors for suicide and suicidal behaviour among Greenland Inuit.

Since the 1970s, suicide has been a major public health issue in Greenland. The World Health Organization has emphasised the importance of the identification of both risk and protective factors in relation to suicide. The aim of this paper was to identify scientific literature on risk and protective factors for suicide and suicidal behaviour among Greenland Inuit. Searches in PubMed and PsycInfo resulted in 420 studies that were screened by three of the authors. After screening, the authors included 15 studies that were subject to quality assessment and data extraction. All 15 studies reported on risk factors, and only three mentioned protective factors. Most reported risk factors were on an individual level and were related to socioeconomic status, mental health, alcohol and substance use, and life stress. Risk factors related to the family mainly related to adverse childhood experiences, while the community level concerned access to education, work, and conflicts. The results indicate a large knowledge gap about protective factors for suicide and suicidal behaviour. The few protective factors reported were related to men having a family, high socioeconomic status, and being born between 1901 and 1950.

Probably the most active population in the world: accelerometer measurements of 72 school-children in Greenland.

Physical activity is the most important lifestyle factor to contribute to a healthy early life. International recommendations are that children should be vigorously physically active for at least 1 h per day, and in Greenland, authorities have claimed a goal of being the world's most active population. Since 1994, the Health Behaviour in School-aged Children (HBSC) has measured physical activity among school-children in Greenland by questionnaire data, but the measurement properties of self-reported data in comparison to more objectively measured accelerometer data are unknown. The present paper describes the first study using clinical measures of physical activity among Greenlandic youth. Seventy-two school-children (56% girls) with a mean age of 12 years (range 25%; 75% was 11.5; 12.25) wore accelerometers for seven consecutive days, and data produced significant and informative findings for both practice and future research. Fifty-two per cent of the school-children met the international recommendations of being physically active >1 h per day, when measured by accelerometers, but self-reported data reported a prevalence of 10% meeting the recommendations. A majority of this sample of Greenlandic school-children lives up to international recommendations, which indicates that the goal of being the world's most active population is within reach.

The effect of diabetes and the diabetogenic TBC1D4 p.Arg684ter variant on kidney function in Inuit in Greenland.

The aim of this study was to examine the effect of diabetes and the diabetogenic TBC1D4 variant on kidney function in Greenland in a population-based setting. Health survey data and TBC1D4 genotypes from 5,336 Greenlanders were used to estimate odds ratios (ORs) of albuminuria (>30 mg/g creatinine) and chronic kidney disease (CKD, eGFR <60 ml/min/1.73m2), comparing individuals with and without diabetes, including the effect of TBC1D4 variant. Of the 3,909 participants with complete data, 9.3% had diabetes. Albuminuria was found in 27.6% and 9.5% and CKD was found in 10.8% and 6.3% among those with and without diabetes, respectively. Diabetes was cross-sectionally associated with an increased risk of albuminuria (OR (95% CI) = 2.37 (1.69,3.33); p < 0.001) and the TBC1D4 variant protected against albuminuria (OR (95% CI) = 0.44 (0.22,0.90); p = 0.02) in a multivariable model. Neither diabetes nor the TBC1D4 variant significantly associated with CKD. The presence/absence of diabetes did not predict changes in eGFR and UACR in longitudinal analyses. Diabetes conferred an increased risk of albuminuria, and the TBC1D4 variant was associated with a decreased risk of albuminuria, but neither was associated with CKD. The potential renoprotective association of the TBC1D4 variant on albuminuria calls for further studies.

A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland.

Background: The genetic disease architecture of Inuit includes a large number of common high-impact variants. Identification of such variants contributes to our understanding of the genetic aetiology of diseases and improves global equity in genomic personalised medicine. We aimed to identify and characterise novel variants in genes associated with Maturity Onset Diabetes of the Young (MODY) in the Greenlandic population. Methods: Using combined data from Greenlandic population cohorts of 4497 individuals, including 448 whole genome sequenced individuals, we screened 14 known MODY genes for previously identified and novel variants. We functionally characterised an identified novel variant and assessed its association with diabetes prevalence and cardiometabolic traits and population impact. Findings: We identified a novel variant in the known MODY gene HNF1A with an allele frequency of 1.9% in the Greenlandic Inuit and absent elsewhere. Functional assays indicate that it prevents normal splicing of the gene. The variant caused lower 30-min insulin (ß = -232 pmol/L, ßSD = -0.695, P = 4.43 × 10-4) and higher 30-min glucose (ß = 1.20 mmol/L, ßSD = 0.441, P = 0.0271) during an oral glucose tolerance test. Furthermore, the variant was associated with type 2 diabetes (OR 4.35, P = 7.24 × 10-6) and HbA1c (ß = 0.113 HbA1c%, ßSD = 0.205, P = 7.84 × 10-3). The variant explained 2.5% of diabetes variance in Greenland. Interpretation: The reported variant has the largest population impact of any previously reported variant within a MODY gene. Together with the recessive TBC1D4 variant, we show that close to 1 in 5 cases of diabetes (18%) in Greenland are associated with high-impact genetic variants compared to 1-3% in large populations. Funding: Novo Nordisk Foundation, Independent Research Fund Denmark, and Karen Elise Jensen's Foundation.