Younger facial looks are associate with a lower likelihood of several age-related morbidities in the middle-aged to elderly.

BACKGROUND: Looking older for one's chronological age is associated with a higher mortality rate. Yet it remains unclear how perceived facial age relates to morbidity and the degree to which facial ageing reflects systemic ageing of the human body. OBJECTIVES: To investigate the association between ΔPA and age-related morbidities of different organ systems, where ΔPA represents the difference between perceived age (PA) and chronological age. METHODS: We performed a cross-sectional analysis on data from the Rotterdam Study, a population-based cohort study in the Netherlands. High-resolution facial photographs of 2679 men and women aged 51.5-87.8 years of European descent were used to assess PA. PA was estimated and scored in 5-year categories using these photographs by a panel of men and women who were blinded for chronological age and medical history. A linear mixed model was used to generate the mean PAs. The difference between the mean PA and chronological age was calculated (ΔPA), where a higher (positive) ΔPA means that the person looks younger for their age and a lower (negative) ΔPA that the person looks older. ΔPA was tested as a continuous variable for association with ageing-related morbidities including cardiovascular, pulmonary, ophthalmological, neurocognitive, renal, skeletal and auditory morbidities in separate regression analyses, adjusted for age and sex (model 1) and additionally for body mass index, smoking and sun exposure (model 2). RESULTS: We observed 5-year higher ΔPA (i.e. looking younger by 5 years for one's age) to be associated with less osteoporosis [odds ratio (OR) 0.76, 95% confidence interval (CI) 0.62-0.93], less chronic obstructive pulmonary disease (OR 0.85, 95% CI 0.77-0.95), less age-related hearing loss (model 2; B = -0.76, 95% CI -1.35 to -0.17) and fewer cataracts (OR 0.84, 95% CI 0.73-0.97), but with better global cognitive functioning (g-factor; model 2; B = 0.07, 95% CI 0.04-0.10). CONCLUSIONS: PA is associated with multiple morbidities and better cognitive function, suggesting that systemic ageing and cognitive ageing are, to an extent, externally visible in the human face.

Prevalence and determinants for xerosis cutis in the middle-aged and elderly population: A cross-sectional study.

BACKGROUND: Determinants and the extent of dry skin in healthy middle-aged and elderly populations have not been well established. OBJECTIVE: We aimed to identify the prevalence and determinants for generalized dry skin (GDS) and localized dry skin (LDS) within a large prospective population-based cohort of middle-aged and elderly individuals of the Rotterdam Study. METHODS: Dry skin was physician-graded as none, localized, or generalized. For GDS and LDS, separate multivariable logistic regression analyses were performed to search for association with participant characteristics, lifestyle factors, environmental factors, several comorbidities, and drug exposure. RESULTS: Among the 5547 eligible participants, 60% had dry skin, of whom a fifth had GDS. Age, female sex, skin color, body mass index, outside temperature, eczema, and chemotherapy in the past were significant determinants for both GDS and LDS. Smoking, the use of statins and diuretics, poorer self-perceived health, and several dermatologic conditions increased the likelihood of having GDS only. Daily cream use was associated with less LDS. LIMITATIONS: Interobserver variability and residual confounding could have influenced our results. Because of our cross-sectional design, we could not infer causality. CONCLUSION: We identified factors significantly associated with dry skin in a general middle-aged and elderly population, with health parameters more strongly associated with GDS.

A healthy diet in women is associated with less facial wrinkles in a large Dutch population-based cohort.

BACKGROUND: Little is known about the effects of different dietary patterns on facial wrinkling. OBJECTIVE: We aimed to investigate the association between diet and facial wrinkles in a population-based cohort of 2753 elderly participants of the Rotterdam study. METHODS: Wrinkles were measured in facial photographs by digitally quantifying the area wrinkles occupied as a percentage of total skin area. Diet was assessed by the Food Frequency Questionnaire. Adherence to the Dutch Healthy Diet Index (DHDI) was calculated. In addition, we used principal component analysis (PCA) to extract relevant food patterns in men and women separately. All food patterns and the DHDI were analyzed for an association with wrinkle severity using multivariable linear regression. RESULTS: Better adherence to the Dutch guidelines was significantly associated with less wrinkles among women but not in men. In women, a red meat and snack-dominant PCA pattern was associated with more facial wrinkles, whereas a fruit-dominant PCA pattern was associated with fewer wrinkles. LIMITATIONS: Due to the cross-sectional design of our study, causation could not be proven. Other health-conscious behaviors of study participants could have influenced the results. CONCLUSION: Dietary habits are associated with facial wrinkling in women. Global disease prevention strategies might benefit from emphasizing that a healthy diet is also linked to less facial wrinkling.

IRF4, MC1R and TYR genes are risk factors for actinic keratosis independent of skin color.

Actinic keratosis (AK) is a pre-malignant skin disease, highly prevalent in elderly Europeans. This study investigates genetic susceptibility to AK with a genome-wide association study (GWAS). A full body skin examination was performed in 3194 elderly individuals from the Rotterdam Study (RS) of exclusive north-western European origin (aged 51-99 years, 45% male). Physicians graded the number of AK into four severity levels: none (76%), 1-3 (14%), 4-9 (6%) and ≥10 (5%), and skin color was quantified using a spectrophotometer on sun-unexposed skin. A GWAS for AK severity was conducted, where promising signals at IRF4 and MC1R (P < 4.2 × 10(-7)) were successfully replicated in an additional cohort of 623 RS individuals (IRF4, rs12203592, Pcombined = 6.5 × 10(-13) and MC1R, rs139810560, Pcombined = 4.1 × 10(-9)). Further, in an analysis of ten additional well-known human pigmentation genes, TYR also showed significant association with AK (rs1393350, P = 5.3 × 10(-4)) after correction for multiple testing. Interestingly, the strength and significance of above-mentioned associations retained largely the same level after skin color adjustment. Overall, our data strongly suggest that IRF4, MC1R and TYR genes likely have pleiotropic effects, a combination of pigmentation and oncogenic functions, resulting in an increased risk of AK.

Genetics of skin color variation in Europeans: genome-wide association studies with functional follow-up.

In the International Visible Trait Genetics (VisiGen) Consortium, we investigated the genetics of human skin color by combining a series of genome-wide association studies (GWAS) in a total of 17,262 Europeans with functional follow-up of discovered loci. Our GWAS provide the first genome-wide significant evidence for chromosome 20q11.22 harboring the ASIP gene being explicitly associated with skin color in Europeans. In addition, genomic loci at 5p13.2 (SLC45A2), 6p25.3 (IRF4), 15q13.1 (HERC2/OCA2), and 16q24.3 (MC1R) were confirmed to be involved in skin coloration in Europeans. In follow-up gene expression and regulation studies of 22 genes in 20q11.22, we highlighted two novel genes EIF2S2 and GSS, serving as competing functional candidates in this region and providing future research lines. A genetically inferred skin color score obtained from the 9 top-associated SNPs from 9 genes in 940 worldwide samples (HGDP-CEPH) showed a clear gradual pattern in Western Eurasians similar to the distribution of physical skin color, suggesting the used 9 SNPs as suitable markers for DNA prediction of skin color in Europeans and neighboring populations, relevant in future forensic and anthropological investigations.

Comprehensive candidate gene study highlights UGT1A and BNC2 as new genes determining continuous skin color variation in Europeans.

Natural variation in human skin pigmentation is primarily due to genetic causes rooted in recent evolutionary history. Genetic variants associated with human skin pigmentation confer risk of skin cancer and may provide useful information in forensic investigations. Almost all previous gene-mapping studies of human skin pigmentation were based on categorical skin color information known to oversimplify the continuous nature of human skin coloration. We digitally quantified skin color into hue and saturation dimensions for 5,860 Dutch Europeans based on high-resolution skin photographs. We then tested an extensive list of 14,185 single nucleotide polymorphisms in 281 candidate genes potentially involved in human skin pigmentation for association with quantitative skin color phenotypes. Confirmatory association was revealed for several known skin color genes including HERC2, MC1R, IRF4, TYR, OCA2, and ASIP. We identified two new skin color genes: genetic variants in UGT1A were significantly associated with hue and variants in BNC2 were significantly associated with saturation. Overall, digital quantification of human skin color allowed detecting new skin color genes. The variants identified in this study may also contribute to the risk of skin cancer. Our findings are also important for predicting skin color in forensic investigations.

Publisher Correction: Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways.

The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.

Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways.

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.

Lifestyle and Physiological Factors Associated with Facial Wrinkling in Men and Women.

Facial wrinkling is one of the most notable signs of skin aging. Men and women show different wrinkling patterns yet the lifestyle and physiological factors underlying these sex-specific patterns are relatively unknown. Here, we investigated sex-specific determinants for facial wrinkles. Wrinkle area was quantified digitally using facial photographs of 3,831 northwestern Europeans (51-98 years, 58% female). Effect estimates from multivariable linear regressions are presented as the percentage difference in the mean value of wrinkle area per unit increase of a determinant (%Δ). Wrinkle area was higher in men (median 4.5%, interquartile range: 2.9-6.3) than in women (3.6%, interquartile range: 2.2-5.6). Age was the strongest determinant, and current smoking (men: 15.5%Δ; women: 30.9%Δ) and lower body mass index (men: 1.7%Δ; women: 1.8%Δ) were also statistically significantly associated with increased wrinkling. Pale skin color showed a protective effect (men: -21.0%Δ; women: -28.5%Δ) and, in men, sunburn tendency was associated with less wrinkling. In women, low educational levels and alcohol use were associated with more wrinkling, whereas female pattern hair loss and a higher free androgen index were associated with less wrinkling. In summary, we validated known and identified additional determinants for wrinkling. Skin aging-reducing strategies should incorporate the sex differences found in this study.

Pigmentation-Independent Susceptibility Loci for Actinic Keratosis Highlighted by Compound Heterozygosity Analysis.

Actinic keratosis (AK) is a skin disease frequently found in European elderly, and it represents the precursor of cutaneous squamous cell carcinoma. Our recent genome-wide association study highlighted DNA variants in two pigmentation genes, IRF4 and MC1R, that confer AK risk in Europeans. Here, we performed a genome-wide search for relaxed forms of compound heterozygosity in association with AK using our recently developed software CollapsABEL. In a discovery dataset of 3,193 Dutch Europeans, a total of 15 genetic loci showed genome-wide significant association with AK (P < 1.25 × 10-10). Of those, three loci (6p21.2, 6p12.2, and 6q13) were confirmed in a replication dataset that included 624 additional Dutch Europeans (P < 0.05). These replicated loci harbored six genes (KCNK5/KCNK17, PAQR8/GSTA2, and KCNQ5/KHDC1), none of them known to be involved in pigmentation. A candidate compound heterozygosity analysis for 12 pigmentation loci highlighted SLC24A4 at 14q32.12 as showing significant association with AK (P = 8.83 × 10-9). The four significantly AK-associated compound heterozygosity single-nucleotide polymorphism pairs together explained 4.37% of the total AK variation, which was 2.62 times greater than the two top-associated individual single nucleotide polymorphisms together (1.67%) identified in the previous conventional genome-wide association study. In conclusion, CollapsABEL showed compound heterozygosity in non-pigmentation- and pigmentation-related loci conferring genetic risk of AK.

A Genome-Wide Association Study Identifies the Skin Color Genes IRF4, MC1R, ASIP, and BNC2 Influencing Facial Pigmented Spots.

Facial pigmented spots are a common skin aging feature, but genetic predisposition has yet to be thoroughly investigated. We conducted a genome-wide association study for pigmented spots in 2,844 Dutch Europeans from the Rotterdam Study (mean age: 66.9±8.0 years; 47% male). Using semi-automated image analysis of high-resolution digital facial photographs, facial pigmented spots were quantified as the percentage of affected skin area (mean women: 2.0% ±0.9, men: 0.9% ±0.6). We identified genome-wide significant association with pigmented spots at three genetic loci: IRF4 (rs12203592, P=1.8 × 10(-27)), MC1R (compound heterozygosity score, P=2.3 × 10(-24)), and RALY/ASIP (rs6059655, P=1.9 × 10(-9)). In addition, after adjustment for the other three top-associated loci the BNC2 locus demonstrated significant association (rs62543565, P=2.3 × 10(-8)). The association signals observed at all four loci were successfully replicated (P<0.05) in an independent Dutch cohort (Leiden Longevity Study n=599). Although the four genes have previously been associated with skin color variation and skin cancer risk, all association signals remained highly significant (P<2 × 10(-8)) when conditioning the association analyses on skin color. We conclude that genetic variations in IRF4, MC1R, RALY/ASIP, and BNC2 contribute to the acquired amount of facial pigmented spots during aging, through pathways independent of the basal melanin production.

Intrinsic and extrinsic risk factors for sagging eyelids.

IMPORTANCE: Sagging eyelids, or dermatochalasis, are a frequent concern in older adults. It is considered a feature of skin aging, but risk factors other than aging are largely unknown. OBJECTIVE: To study nongenetic and genetic risk factors for sagging eyelids. DESIGN: Upper eyelid sagging was graded in 4 categories of severity using digital photographs. Dermatochalasis was defined as the eyelid hanging over the eyelashes. Age, sex, skin color, tanning ability, hormonal status in women, current smoking, body mass index, and sun protection behavior were analyzed in a multivariable multinomial logistic regression model. Genetic predisposition was assessed using heritability analysis and a genome-wide association study. SETTING AND PARTICIPANTS: The study was performed in 2 independent population-based cohorts. The Rotterdam Study included older adults from one district in Rotterdam, the Netherlands, and the UK Adult Twin Registry (TwinsUK) included twins from all over the United Kingdom. Participants were 5578 unrelated Dutch Europeans (mean age, 67.1 years; 44.0% male) from the Rotterdam Study and 2186 twins (mean age, 53.1 years; 10.4% male) from the TwinsUK. MAIN OUTCOMES AND MEASURES: Sagging eyelid severity levels, ranging from 1 (normal control) to 4 (severe sagging). RESULTS: Among 5578 individuals from the Rotterdam Study, 17.8% showed dermatochalasis (moderate and severe sagging eyelids). Significant and independent risk factors for sagging eyelids included age, male sex, lighter skin color, and higher body mass index. In addition, current smoking was borderline significantly associated. Heritability of sagging eyelids was estimated to be 61% among 1052 twin pairs from the TwinsUK (15.6% showed dermatochalasis). A meta-analysis of genome-wide association study results from 5578 Rotterdam Study and 1053 TwinsUK participants showed a genome-wide significant recessive protective effect of the C allele of rs11876749 (P = 1.7 × 10(-8)). This variant is located close to TGIF1 (an inducer of transforming growth factor ß), which is a known gene associated with skin aging. CONCLUSIONS AND RELEVANCE: This is the first observational study to date demonstrating that other risk factors (male sex, genetic variants, lighter skin color, high body mass index, and possibly current smoking) in addition to aging are involved in the origin of sagging eyelids.

Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.

Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.

Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.

Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.