Anderson, Karen

Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism ( MACROD2 ), development ( NEDD4 ), and mental retardation ( UBE2A ) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.

Background The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study has sustained an extraordinarily high level of participant involvement for over two decades. Purpose In order to identify specific characteristics of EDIC that contributed most strongly to retention, study-designed questionnaires were distributed to 1334 participants. Methods Confidential questionnaires were completed during EDIC Years 15–17. Participants were classified as Completely Adherent (completed all visits), Partly Adherent (missed >1 visit or major portion of a visit), or Inactive (did not participate for >5 years). Questionnaire items addressed specific aspects of clinic visits, evaluation procedures, staff–participant relationships, and medical/health-care support provided by EDIC. Results The most commonly cited reasons for continuing participation were Cutting Edge Tests to assess diabetes complications (79.3%), Annual Evaluations (67.7%), a desire to Help Others (65.2%), and Better Care for Diabetes (61.6%). Women chose Cutting Edge Tests as their first or second most important reason significantly more often than men, whereas men chose Better Care for Diabetes more frequently. Individuals with at least three diabetes-related complications were more likely than those with fewer complications to choose Annual Evaluations as their first or second reason for continued involvement. Limitations The small proportion of individuals who discontinued participation restricted our ability to identify factors associated with suspended involvement. In addition, our analysis is limited to a cohort with type 1 diabetes followed in an observational study after an average participation time of 6.5 years in a randomized trial. Conclusions The primary reasons identified by respondents for their long-term commitment are consistent with shorter-term studies and underscore the importance of expert medical care, supportive staff–participant relationships, and involvement with clinically and scientifically meaningful research.

A recently identified variant within the fat mass and obesity-associated ( FTO ) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobes—these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.